{"gene":"IL22","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2000,"finding":"IL-22 (originally termed IL-TIF) was identified as a novel cytokine structurally related to IL-10; it signals through a two-component receptor complex consisting of CRF2-9 (IL-22R1) and IL-10R2 (CRF2-4), activating STAT1, STAT3, and STAT5 in responsive cell lines but not inhibiting LPS-induced proinflammatory cytokines in monocytes, distinguishing it functionally from IL-10.","method":"Receptor binding assays, STAT activation assays in cell lines, functional cytokine production assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — original discovery paper with receptor identification and signaling characterization, replicated in multiple cell lines","pmids":["10875937"],"is_preprint":false},{"year":2000,"finding":"Mouse IL-TIF (IL-22) was cloned and shown to be induced by IL-9 in T cells and mast cells; recombinant protein activated STAT1 and STAT3 in hepatoma cells and stimulated acute phase reactants (serum amyloid A, alpha1-antichymotrypsin, haptoglobin) in HepG2 hepatoma cells; anti-IL-10R2 antibody blocked IL-22-induced acute phase reactant induction, establishing IL-10R2 as a shared receptor chain.","method":"cDNA subtraction cloning, recombinant protein stimulation, Western blot for STAT activation, antibody blockade","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1 — original cloning with functional characterization and receptor blocking experiments","pmids":["10657629"],"is_preprint":false},{"year":2000,"finding":"The functional IL-22 receptor complex was identified as a heterodimer of the orphan CRF2-9 chain (IL-22R1) and IL-10R2; each chain can independently bind IL-22 but cooperative binding occurs with the complex; the CRF2-9 intracellular domain is responsible for STAT recruitment, and substitution with IFN-gammaR1 intracellular domain changes the STAT activation pattern.","method":"COS cell expression of receptor chains, hamster cell reconstitution, radiolabeled IL-22 cross-linking, intracellular domain swap experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — receptor reconstitution with domain swap mutagenesis confirming functional mechanism","pmids":["11035029"],"is_preprint":false},{"year":2000,"finding":"Human IL-TIF (IL-22) was cloned; recombinant protein activated STAT1 and STAT3 in hepatoma cell lines and stimulated acute phase reactants; anti-IL-10R2 antibodies blocked IL-22-induced acute phase reactant induction, confirming IL-10R2 as a shared receptor chain for IL-10 and IL-22.","method":"cDNA cloning, STAT activation assays, ELISA for acute phase proteins, antibody neutralization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — human gene cloning with receptor blockade and functional characterization","pmids":["10954742"],"is_preprint":false},{"year":2002,"finding":"IL-22 activates JAK1 and Tyk2 (but not JAK2), and phosphorylates STAT1, STAT3, and STAT5 on tyrosine residues in rat hepatoma H4IIE cells; additionally IL-22 activates all three major MAPK pathways (ERK1/2, JNK, p38); IL-22 also induces serine phosphorylation of STAT3 on Ser727 independently of MEK1/2, and a STAT3 S727A mutant shows reduced transactivation, establishing that Ser727 phosphorylation is required for maximum STAT3 transcriptional activity downstream of IL-22.","method":"Immunoblot with phospho-specific antibodies, kinase-specific inhibitors, STAT3 S727A mutant overexpression, transcriptional reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro signaling pathway dissection with mutagenesis and pharmacological inhibitors","pmids":["12087100"],"is_preprint":false},{"year":2003,"finding":"Mouse IL-22 binding protein (mIL-22BP) was cloned; it binds both mouse and human IL-22 and neutralizes STAT3 activation induced by IL-22 in human and rat hepatoma cell lines; mIL-22BP blocks IL-22-induced reactive oxygen species production in B cells; mIL-22BP expression is upregulated by LPS in mouse monocytes.","method":"Genomic library screening, RT-PCR, binding assays, STAT3 activation assays, ROS measurement","journal":"Genes and immunity","confidence":"High","confidence_rationale":"Tier 1-2 — functional receptor characterization with binding and signaling neutralization assays","pmids":["12700595"],"is_preprint":false},{"year":2004,"finding":"Mouse and rat homologs of IL-22Rα2 (IL-22 binding protein) were identified; like human IL-22Rα2, they exist only as soluble receptors lacking transmembrane and intracellular domains; the murine gene is located between IFNGR1 and IL-20R1 genes (syntenic with human); IL-22Rα2 mRNA shows limited tissue distribution and differential modulation during systemic inflammation in spleen, thymus, and lymph node.","method":"Genomic sequence analysis, RT-PCR, quantitative expression analysis","journal":"Genes and immunity","confidence":"Medium","confidence_rationale":"Tier 2 — structural and expression characterization without full functional reconstitution","pmids":["15201862"],"is_preprint":false},{"year":2004,"finding":"IL-22 receptor (IL-22R1) expression is highly restricted, with highest expression in pancreatic acinar cells, and lower functional levels in skin, colon, liver, and kidney; IL-22 signals through a heterodimer of IL-22R1 and CRF2-4/IL-10Rb; IL-22 induces acute-phase-type responses resembling IL-6 activity.","method":"Expression analysis, receptor characterization, functional cytokine assays","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 — receptor expression mapping with functional characterization","pmids":["15120651"],"is_preprint":false},{"year":2004,"finding":"IL-22 is a survival factor for hepatocytes acting via STAT3 activation: IL-22 blockade worsened T cell-mediated hepatitis whereas recombinant IL-22 attenuated it; stable overexpression of IL-22 in HepG2 cells constitutively activated STAT3 and induced antiapoptotic proteins (Bcl-2, Bcl-xL, Mcl-1) and mitogenic proteins (c-myc, cyclin D1, CDK4); blocking STAT3 activation abolished IL-22's antiapoptotic and mitogenic actions.","method":"Neutralizing antibody in vivo, recombinant cytokine injection, stable overexpression, STAT3 inhibition, Western blot for downstream targets","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal approaches (in vivo neutralization, in vitro overexpression, STAT3 blockade) confirming the mechanism","pmids":["15122762"],"is_preprint":false},{"year":2005,"finding":"IL-22 activates NF-κB and AP-1 within 1 hour in colonic subepithelial myofibroblasts (SEMFs) and induces expression of proinflammatory cytokines (IL-6, IL-8, IL-11, LIF) and matrix metalloproteinases; NF-κB and AP-1 blockade markedly reduced these effects; MAP kinase inhibitors (PD98059, SB202190) significantly reduced IL-22-induced cytokine secretion; IL-17 plus IL-22, or IL-19 plus IL-22, additively upregulated cytokine secretion.","method":"cDNA microarray, Northern blot, ELISA, EMSA for NF-κB/AP-1, pharmacological inhibitors","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple pathway inhibition experiments with mechanistic readouts","pmids":["16143135"],"is_preprint":false},{"year":2006,"finding":"IL-22 binds to its receptor complex (IL-22R1 and IL-10R2) on intestinal epithelial cell (IEC) lines, activating STAT1/3, Akt, ERK1/2, and SAPK/JNK MAP kinases; IL-22 increased IEC proliferation and phosphatidylinositol 3-kinase (PI3K)-dependent IEC migration; TNF-α, IL-1β, and LPS upregulated IL-22R1 but not IL-10R2 expression; IL-22 induced TNF-α, IL-8, and human beta-defensin-2 expression in IECs.","method":"Western blot for signaling pathways, proliferation assay, PI3K inhibitor treatment, wounding/migration assay, RT-PCR","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 1-2 — comprehensive signaling pathway mapping with PI3K inhibitor mechanistic confirmation","pmids":["16537974"],"is_preprint":false},{"year":2008,"finding":"IL-22 mediates mucosal host defense against Klebsiella pneumoniae: IL-22 increased lung epithelial cell proliferation and transepithelial resistance to injury; both IL-22 and IL-17A regulated CXC chemokine and G-CSF production in the lung, but only IL-22 promoted epithelial barrier protection.","method":"Mouse infection model with IL-22 and IL-17A neutralization/KO, epithelial barrier assays, chemokine measurement","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic and antibody blockade with specific epithelial phenotypic readouts","pmids":["18264110"],"is_preprint":false},{"year":2008,"finding":"A human NK cell subset (NK-22 cells) located in mucosa-associated lymphoid tissues is hard-wired to secrete IL-22, IL-26, and LIF; these cells are triggered by IL-23 exposure; NK-22-secreted cytokines stimulate epithelial cells to secrete IL-10, proliferate, and express mitogenic and anti-apoptotic molecules in vitro; NK-22 cells appear in mouse small intestine lamina propria during bacterial infection.","method":"Cell isolation and characterization, cytokine stimulation assays, in vitro epithelial cell co-culture, in vivo bacterial infection model","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods identifying a new cellular source and functional consequence of IL-22","pmids":["18978771"],"is_preprint":false},{"year":2011,"finding":"Aryl hydrocarbon receptor (AhR) signaling upregulates IL-22 production and inhibits intestinal inflammation: AhR agonist (Ficz) reduced IFN-γ and upregulated IL-22 in intestinal lamina propria mononuclear cells from IBD patients; in vivo Ficz protected mice against TNBS-, DSS-, and T-cell-transfer-induced colitis with marked induction of IL-22; AhR antagonist reduced IL-22 and worsened colitis; neutralization of endogenous IL-22 disrupted the protective effect of Ficz, placing AhR upstream of IL-22 in this pathway.","method":"In vitro cytokine production assays, multiple in vivo colitis models with AhR agonist/antagonist, IL-22 neutralizing antibody epistasis experiment","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 — multiple models plus IL-22 neutralization epistasis establishing AhR→IL-22 pathway","pmids":["21600206"],"is_preprint":false},{"year":2013,"finding":"IL-22 directly induces goblet cell hyperplasia and expression of goblet cell markers including mucins in intestinal epithelial cells ex vivo and in vitro; IL-22-deficient mice show impaired worm expulsion and reduced goblet cell hyperplasia after Nippostrongylus brasiliensis or Trichuris muris infection despite normal type 2 cytokine production.","method":"IL-22 KO mouse infection model, ex vivo and in vitro epithelial stimulation, goblet cell marker quantification","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 — genetic KO combined with in vitro direct stimulation establishing IL-22 → goblet cell hyperplasia mechanism","pmids":["24130494"],"is_preprint":false},{"year":2014,"finding":"IL-22 promotes intestinal epithelial cell regeneration after acute kidney injury (AKI) via TLR4 signaling: necrotic tubular cells and oxidative stress induced IL-22 secretion selectively through TLR4; IL-22 deficiency or blockade impaired post-ischemic tubular recovery; TLR4 blockade during healing phase suppressed IL-22 production and impaired kidney regeneration; IL-22 receptor is expressed exclusively by tubular epithelial cells while IL-22 is secreted by interstitial dendritic cells and macrophages.","method":"IL-22 KO mice, IL-22 blockade, TLR4 blockade, cell depletion/reconstitution experiments, in vitro tubular cell recovery assay","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic and pharmacological interventions with rescue experiments establishing TLR4→IL-22→tubular repair pathway","pmids":["24459235"],"is_preprint":false},{"year":2014,"finding":"IL-22-producing CD4+ T cells promote colorectal cancer stemness via STAT3 activation and induction of the histone methyltransferase DOT1L; IL-22-activated STAT3 drives DOT1L expression which induces core stem cell genes NANOG, SOX2, and Pou5F1, increasing cancer stemness; CCR6/CCL20 chemokine axis mediates migration of IL-22-producing CD4+ T cells into the colon cancer microenvironment.","method":"Patient tissue analysis, mouse colon cancer model, STAT3 activation assays, DOT1L expression analysis, stem cell gene expression, CCR6 KO experiments","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway from IL-22→STAT3→DOT1L→stemness genes established in vitro and in vivo","pmids":["24816405"],"is_preprint":false},{"year":2014,"finding":"IL-22 protects mice from acetaminophen-induced liver injury (AILI) acutely through STAT3 activation (IL-22 failed to protect in liver-specific STAT3 KO mice); however, chronic constitutive IL-22 overexpression exacerbates AILI by upregulating CYP2E1 via elevated HNF-1α; CYP2E1 ablation but not hepatic STAT3 deletion abolished AILI enhancement in IL-22 transgenic mice.","method":"Liver-specific STAT3 KO, IL-22 transgenic mice, IL-22 adenovirus treatment, CYP2E1 KO, HNF-1α expression analysis","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1-2 — multiple tissue-specific KO models with opposing temporal mechanisms genetically dissected","pmids":["25063867"],"is_preprint":false},{"year":2014,"finding":"IL-21 induces IL-22 production by CD4+ T cells through STAT3, which controls the epigenetic status of the il22 promoter and its interaction with the aryl hydrocarbon receptor (AhR); IL-21 and AhR signaling in T cells cooperate to control IL-22 production and dextran sodium sulfate-induced colitis in ILC-deficient mice.","method":"In vitro T cell stimulation, STAT3 activation and chromatin analysis, AhR interaction assays, in vivo colitis model in ILC-deficient mice","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — epigenetic mechanism with in vivo validation linking IL-21/STAT3/AhR to IL-22 production","pmids":["24796415"],"is_preprint":false},{"year":2015,"finding":"Intestinal epithelial cell (IEC)-specific Tyrosine kinase 2 (Tyk2) transduces IL-22 signals to protect from acute colitis: Tyk2-deficient primary IECs show reduced STAT3 phosphorylation in response to IL-22; IEC-specific Tyk2 KO mice develop more severe colitis with less pSTAT3 in colon tissue and reduced IEC proliferation; disease can be alleviated by high-dose rIL-22-Fc, indicating Tyk2 deficiency is overcome by increased receptor engagement.","method":"Conditional Tyk2 KO mice, primary IEC stimulation with IL-22, pSTAT3 assays, colitis model with Citrobacter rodentium","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 — IEC-specific conditional KO with mechanistic rescue establishing Tyk2 as IL-22 signal transducer","pmids":["26432894"],"is_preprint":false},{"year":2015,"finding":"IL-22 signaling in the liver during pneumococcal pneumonia promotes host defense by increasing hepatic C3 complement expression; IL-22 administration increased C3 binding on S. pneumoniae surfaces (opsonization); mice with hepatic-specific deletion of IL-22Ra1 had higher bacterial burdens, establishing that IL-22 → hepatic C3 → bacterial opsonization is a key defense mechanism.","method":"Hepatic-specific IL-22Ra1 KO mice, recombinant IL-22 administration, C3 expression assays, opsonic killing assays","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific KO with mechanistic pathway identification through complement pathway","pmids":["27456484"],"is_preprint":false},{"year":2016,"finding":"Human IL-22 binding protein (IL-22BP) exists in three isoforms generated by alternative splicing with distinct functions: IL-22BPi2 has greater inhibitory activity than IL-22BPi3; IL-22BPi1 is not secreted and fails to antagonize IL-22; IL-22BPi2 is selectively increased by TLR2 signaling and retinoic acid in myeloid cells; IL-22BPi2 more effectively blocks IL-22/IL-17 cooperative gene induction than IL-22BPi3, functioning as a rheostat for IL-22/STAT3 responses.","method":"Isoform-specific expression constructs, secretion assays, IL-22 STAT3 reporter assays, TLR2 and retinoic acid stimulation of myeloid cells","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1-2 — functional characterization of all three isoforms with mechanistic dissection of differential inhibitory activities","pmids":["27678220"],"is_preprint":false},{"year":2017,"finding":"IL-18 drives ILC3 proliferation and IL-22 production via NF-κB: the NF-κB complex component p65 binds to the proximal region of the IL22 promoter and promotes transcriptional activity; IL-18 cooperates with IL-15 to induce human ILC3 proliferation and IL-22 production; CD11c+ dendritic cells expressing IL-18 are found in close proximity to ILC3s in human tonsils.","method":"NF-κB p65 ChIP assay at IL22 promoter, ILC3 proliferation assays, IL-22 production measurement, in situ proximity analysis in tonsil tissue","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP assay establishing direct p65 binding to IL22 promoter plus functional validation","pmids":["28842466"],"is_preprint":false},{"year":2014,"finding":"IL-22 directly induces keratinocyte proliferation and epidermal hyperplasia, inhibits terminal differentiation, and promotes production of antimicrobial proteins in the skin; IL-22 and TNF-α act synergistically on keratinocytes in proinflammatory Th22 responses; wound healing in an in vitro injury model is exclusively dependent on IL-22 from Th22 supernatants.","method":"Primary keratinocyte cultures, Th22 cell supernatant stimulation, wound healing assay, neutralizing antibody experiments","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — specific IL-22 neutralization demonstrates exclusive role in wound healing mechanism","pmids":["19920355"],"is_preprint":false},{"year":2011,"finding":"IL-22 promotes human hepatocellular carcinoma growth via STAT3 activation: IL-22 induces phosphorylation of STAT3 and upregulates downstream genes Bcl-2, Bcl-xL, CyclinD1, and VEGF in HCC cells; tumor formation was significantly decreased in IL-22 knockout mice in a diethylnitrosamine-induced HCC model.","method":"IL-22 KO mouse HCC model, STAT3 phosphorylation assays, downstream target gene expression, in vivo subrenal cotransplantation experiments","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 — IL-22 KO in vivo model combined with STAT3 pathway characterization","pmids":["21674558"],"is_preprint":false},{"year":2014,"finding":"IL-22 signals through pSTAT3 binding to the Il-18 gene promoter to induce epithelial IL-18 production, placing IL-22-STAT3 signaling upstream of IL-18-mediated intestinal barrier defense; in organoids, IL-22 primarily increases size and inhibits stem cell genes while IL-18 preferentially promotes organoid budding via Akt-Tcf4 signaling; systemic IL-18 corrects compromised T-cell IFNγ and Paneth cells in Il-22-/- mice during AIEC infection, but IL-22 fails to restore these in Il-18-/- mice.","method":"ChIP (pSTAT3 at Il-18 promoter), intestinal organoid culture, IL-22 and IL-18 KO mice, AIEC infection model, genetic epistasis experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP establishing direct STAT3 binding plus genetic epistasis placing IL-22 upstream of IL-18","pmids":["35169117"],"is_preprint":false},{"year":2018,"finding":"High IL-22 levels inhibit ileal intestinal stem cell (ISC) expansion in favor of transit-amplifying (TA) progenitor expansion; IL-22Ra1 is expressed on only a subset of ISCs and TA progenitors; IL-22 reduces ISC biomarker expression, self-renewal pathway activity, and ISC expansion without causing major differentiation defects; in vivo, chronic IL-22 overexpression (IL-22 transgenic mice) increases TA zone proliferative cells without increasing ISC numbers.","method":"Ileal mouse organoid screen, single-cell RNA sequencing for Il22ra1 expression, ISC serial passaging assay, IL-22 transgenic mouse analysis","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"High","confidence_rationale":"Tier 2 — organoid functional assays combined with in vivo transgenic model and single-cell receptor mapping","pmids":["30364840"],"is_preprint":false},{"year":2014,"finding":"IL-22 inhibits keratinocyte terminal differentiation and reduces expression of C/EBPα; IL-22 induces phosphorylation of JNK, ERK, and p38 via the MAPK signaling pathway in keratinocytes; siRNA knockdown of C/EBPα phenocopies IL-22's proliferative effect, increasing keratinocyte proliferation and reducing cytokeratin 10 and involucrin expression.","method":"Keratinocyte stimulation with recombinant IL-22, Western blot for phospho-MAPK, qRT-PCR, CCK-8 proliferation assay, C/EBPα siRNA knockdown","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — pharmacological pathway analysis plus siRNA confirming C/EBPα as mediator","pmids":["32945375"],"is_preprint":false},{"year":2014,"finding":"IL-22 activates STAT3 in keratinocytes, and phosphorylated STAT3 binds to sequences in the putative miR-197 promoter inducing miR-197 expression; miR-197 overexpression inhibits IL-22-induced keratinocyte proliferation and migration; miR-197 directly targets IL-22RA1 (IL-22 receptor subunit), creating a negative feedback loop where IL-22 induces miR-197 which in turn downregulates IL-22 receptor and attenuates IL-22 signaling.","method":"Luciferase reporter assay, STAT3 ChIP at miR-197 promoter, miR-197 overexpression, migration assays, IL22RA1 3'UTR targeting validation","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP for STAT3 binding plus functional validation of the feedback loop with receptor targeting","pmids":["25208211"],"is_preprint":false},{"year":2017,"finding":"Prostaglandin E2 (PGE2) induces IL-22 production from T cells through EP2 and EP4 receptors via cyclic AMP signaling; selective deletion of EP4 in T cells prevents hapten-induced IL-22 production in vivo and limits atopic-like skin inflammation in the oxazolone-induced allergic contact dermatitis model.","method":"T-cell cultures with PGE2 and receptor-specific agonists/antagonists, T cell-specific EP4 KO mice, in vivo hapten sensitization model","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 — T cell-specific KO with in vivo phenotypic readout establishing PGE2→EP4→cAMP→IL-22 pathway","pmids":["28583370"],"is_preprint":false},{"year":2020,"finding":"Microbiota-derived short-chain fatty acids (SCFAs) promote IL-22 production by CD4+ T cells and ILCs through G-protein receptor 41 (GPR41) and HDAC inhibition; SCFAs upregulate IL-22 by promoting aryl hydrocarbon receptor (AhR) and HIF1α expression; HIF1α binds directly to the Il22 promoter, and SCFAs increase HIF1α binding through histone modification; mTOR and Stat3 differentially regulate AhR and HIF1α expression.","method":"GPR41 KO, HDAC inhibitor studies, ChIP for HIF1α at Il22 promoter, mTOR/STAT3 inhibition, histone modification assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP establishing direct HIF1α binding to Il22 promoter combined with multiple genetic and pharmacological approaches","pmids":["32901017"],"is_preprint":false},{"year":2020,"finding":"IL-22 is required for the development of colitis in Il10-/- mice: Il10-/-Il22-/- double KO mice did not develop colitis despite retaining high levels of Th17 cells and colitogenic Helicobacter spp.; IL-22-driven IEC hyperplasia and Reg3g antimicrobial gene expression were reversed in double KO mice; IL-22 shaped the fecal microbiome diversity in Il10-/- mice.","method":"Il10-/-Il22-/- double KO genetic model, histology, antimicrobial gene expression, 16S microbiome analysis","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 — clean double-KO genetic model revealing epistatic relationship between IL-10 and IL-22 in colitis","pmids":["31932715"],"is_preprint":false},{"year":2019,"finding":"IFN-I acts on intestinal epithelial cells during murine norovirus infection to increase CCR2-dependent macrophages and IL-22-producing innate lymphoid cells; IL-22 then promotes pSTAT3 signaling in intestinal epithelial cells and protection from intestinal injury; MNV provides striking IL-22-dependent protection against Citrobacter rodentium lethal infection in neonates.","method":"MNV infection model, IFN-I signaling analysis, IL-22 KO mice, ILC characterization, STAT3 signaling assays","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 — IL-22 KO genetic model with mechanistic pathway analysis in viral infection context","pmids":["31182797"],"is_preprint":false},{"year":2022,"finding":"TNF induces IL-22Ra2 (IL-22BP, a soluble IL-22 antagonist) in colonic dendritic cells, thereby restricting IL-22 bioavailability and abrogating IL-22/STAT3-mediated mucosal repair during colitis; membrane-bound TNF from T cells perpetuates colonic inflammation while soluble TNF from epithelial cells specifically drives IL-22BP expression in colonic DCs; anti-TNF therapy increases IL-22 availability, explaining mucosal healing.","method":"Humanized colitis model, TNF source identification, IL-22BP induction assays in DCs, IL-22/STAT3 signaling readouts, correlation of IL-22BP with TNF in IBD patient sera","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection of TNF sources and IL-22BP induction with functional STAT3 signaling readouts","pmids":["35383266"],"is_preprint":false},{"year":2024,"finding":"Recombinant IL-22 resolves MASLD by acting through its IEC receptor (not hepatocytes) to activate STAT3 and inhibit WNT-β-catenin signaling in intestinal epithelial cells, thereby shrinking the absorptive enterocyte compartment and reversing macronutrient absorption; this mechanism reversed hepatosteatosis, inflammation, fibrosis, and insulin resistance; obesogenic diets suppress IL-22 production by small intestine innate lymphocytes, causing STAT3 inhibition in IECs.","method":"Recombinant IL-22 treatment, IEC-specific receptor studies, STAT3 and WNT-β-catenin signaling analysis, intestinal morphometric analysis, diet-induced MASLD mouse model","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 — receptor-specific pathway dissection (IEC vs hepatocyte) with mechanistic signaling readouts in disease model","pmids":["39317186"],"is_preprint":false},{"year":2010,"finding":"IL-22 provides antifungal defense against Candida albicans independent of IL-17A/F, controlling yeast growth and contributing to epithelial integrity; IL-22 is upregulated under Th1-deficient conditions; in IL-17RA-deficient mice (where IL-17A contributes to susceptibility), IL-22 mediates protection against candidiasis.","method":"IL-17RA KO mice, IL-22 neutralization, Candida albicans infection model, epithelial integrity assays","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO and antibody neutralization models establishing IL-22's independent antifungal pathway","pmids":["20445503"],"is_preprint":false},{"year":2016,"finding":"IL-22 and cyclosporine A (CSA) cooperate to promote squamous cell carcinoma (SCC): CSA drives T cell polarization toward IL-22-producing T22 cells and increases IL-22 receptor expression on SCC cells; IL-22 combined with CSA increased SCC cell migration and invasion; anti-IL-22 antibody reduced tumor number and tumor burden in a UV-induced SCC mouse model.","method":"T cell polarization assays, SCC cell invasion/migration assays, UV-induced SCC mouse model with anti-IL-22 antibody treatment","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2-3 — in vivo antibody blockade with in vitro mechanistic studies","pmids":["27699266"],"is_preprint":false},{"year":2019,"finding":"IL-17 and IL-22 together promote keratinocyte stemness in psoriasis by inducing upregulation of stemness markers (p63, CD44, CD29), increasing colony-forming efficiency and long-term proliferative capacity, and promoting an immature differentiation state; IL-22 induces these effects by acting directly on keratinocytes.","method":"Flow cytometry on lesional keratinocytes, cytokine treatment of normal keratinocytes, colony-forming efficiency assay","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 3 — in vitro cytokine treatment with functional stemness readouts but no genetic pathway dissection","pmids":["30684548"],"is_preprint":false}],"current_model":"IL-22 is a secreted cytokine that signals through a heterodimeric receptor complex (IL-22R1/CRF2-9 and IL-10R2), activating JAK1 and Tyk2, leading to STAT1, STAT3, and STAT5 tyrosine phosphorylation as well as ERK, JNK, and p38 MAPK pathways; STAT3 Ser727 phosphorylation is additionally required for maximal transcriptional activity; the primary mechanistic outputs of IL-22-STAT3 signaling in epithelial cells include induction of antimicrobial peptides, mucins, and acute phase reactants, promotion of epithelial proliferation and barrier integrity (via Tyk2), goblet cell hyperplasia, hepatocyte survival through antiapoptotic gene induction, and organ regeneration; IL-22 production is regulated upstream by AhR, STAT3 (via IL-21), NF-κB (via IL-18), HIF1α (via SCFAs/GPR41/HDAC inhibition), and PGE2/EP4/cAMP signaling, while its bioavailability is limited by soluble IL-22BP (IL-22Ra2) isoforms that act as a rheostat and are induced by TNF in dendritic cells; IL-22 further initiates an IL-22→STAT3→IL-18 epithelial response circuit that promotes intestinal stem cell expansion and barrier defense, and a negative feedback loop via STAT3-induced miR-197 that targets IL-22Ra1 to attenuate signaling."},"narrative":{"teleology":[{"year":2000,"claim":"The identity of IL-22 as a new IL-10 family cytokine and its two-chain receptor complex (IL-22R1/IL-10R2) were established, resolving the molecular basis for its signaling through STAT1, STAT3, and STAT5 and distinguishing it functionally from IL-10.","evidence":"Receptor binding, STAT activation assays, and anti-IL-10R2 blocking in hepatoma cell lines and COS cell reconstitution with domain-swap mutagenesis","pmids":["10875937","10657629","10954742","11035029"],"confidence":"High","gaps":["Crystal structure of the ternary IL-22/receptor complex was not resolved","Tissue-level receptor distribution was incompletely mapped","Relative contributions of each receptor chain to downstream signaling specificity were not fully defined"]},{"year":2002,"claim":"The full intracellular signaling cascade downstream of IL-22 was mapped—JAK1/Tyk2 activation, STAT1/3/5 tyrosine phosphorylation, ERK/JNK/p38 MAPK, and the requirement for STAT3 Ser727 phosphorylation for maximal transcriptional activity—establishing the signaling framework underlying all subsequent functional studies.","evidence":"Phospho-specific immunoblots, kinase inhibitors, and STAT3 S727A mutant reporter assays in rat hepatoma cells","pmids":["12087100"],"confidence":"High","gaps":["Kinase responsible for STAT3 Ser727 phosphorylation downstream of IL-22 was not identified","Contribution of individual MAPK branches to specific gene programs remained unclear"]},{"year":2004,"claim":"IL-22 was shown to be a hepatocyte survival factor acting through STAT3 to induce antiapoptotic (Bcl-2, Bcl-xL, Mcl-1) and mitogenic (c-myc, cyclin D1) genes, establishing its cytoprotective role in the liver.","evidence":"In vivo IL-22 neutralization worsening T-cell hepatitis, stable IL-22 overexpression in HepG2 cells, STAT3 blockade abolishing effects","pmids":["15122762"],"confidence":"High","gaps":["Whether STAT3-independent pathways contribute to hepatoprotection was not tested","Duration and dose-dependence of protective versus potentially oncogenic STAT3 activation were unexplored"]},{"year":2005,"claim":"Beyond hepatocytes, IL-22 was found to activate NF-κB and AP-1 in colonic subepithelial myofibroblasts, inducing proinflammatory cytokines and MMPs, revealing that IL-22 has pro-inflammatory outputs in mesenchymal cells in addition to its epithelial effects.","evidence":"EMSA for NF-κB/AP-1, MAPK inhibitors, ELISA in colonic myofibroblast cultures","pmids":["16143135"],"confidence":"High","gaps":["In vivo relevance of myofibroblast-directed signaling to intestinal pathology was not demonstrated","Relative contribution of NF-κB versus AP-1 to specific gene targets was not resolved"]},{"year":2006,"claim":"IL-22 was shown to act directly on intestinal epithelial cells to drive proliferation, PI3K-dependent migration, and antimicrobial peptide (hBD-2) expression, establishing the intestinal epithelium as a primary target tissue.","evidence":"Signaling pathway analysis, PI3K inhibitor migration assay, and cytokine/defensin induction in IEC lines","pmids":["16537974"],"confidence":"High","gaps":["In vivo validation of PI3K-dependent migration in wound healing was lacking","Receptor expression regulation in primary human IECs was not confirmed"]},{"year":2008,"claim":"The in vivo mucosal protective function of IL-22 was established in lung and gut: IL-22 protected lung epithelial barriers during Klebsiella pneumonia and was identified as the signature cytokine of mucosal NK-22 cells triggered by IL-23.","evidence":"IL-22 neutralization/KO in Klebsiella infection model; isolation and functional characterization of NK-22 cells from human tonsil and mouse lamina propria","pmids":["18264110","18978771"],"confidence":"High","gaps":["Relative contributions of NK-22 versus Th17/ILC3 sources to total mucosal IL-22 were not quantified","Mechanism of IL-22-mediated transepithelial resistance increase was not molecularly defined"]},{"year":2011,"claim":"AhR was positioned upstream of IL-22 as a key transcriptional regulator: AhR agonism induced IL-22 and protected from experimental colitis, and IL-22 neutralization abolished the AhR-mediated protection, establishing the AhR→IL-22 axis. Separately, IL-22/STAT3 signaling was shown to promote hepatocellular carcinoma growth.","evidence":"AhR agonist/antagonist in multiple colitis models with IL-22 epistasis; IL-22 KO in diethylnitrosamine HCC model","pmids":["21600206","21674558"],"confidence":"High","gaps":["Direct AhR binding to the IL22 promoter was not demonstrated in this study","Thresholds distinguishing protective versus tumorigenic IL-22/STAT3 activity were undefined"]},{"year":2013,"claim":"IL-22 was found to directly induce goblet cell hyperplasia and mucin expression, and IL-22 KO mice showed impaired helminth expulsion, expanding the repertoire of IL-22 epithelial outputs beyond antimicrobial peptides to mucus barrier defense.","evidence":"IL-22 KO mice infected with Nippostrongylus brasiliensis and Trichuris muris, ex vivo and in vitro epithelial stimulation","pmids":["24130494"],"confidence":"High","gaps":["Transcription factors mediating IL-22-driven goblet cell differentiation were not identified","Whether IL-22 acts on goblet cell progenitors or mature goblet cells was not resolved"]},{"year":2014,"claim":"Multiple regulatory and effector mechanisms converged: IL-21/STAT3 was shown to epigenetically control the IL22 locus in cooperation with AhR; IL-22→STAT3→DOT1L drove cancer stemness genes; IL-22→STAT3 directly induced IL-18 via promoter binding creating an epithelial defense circuit; and a STAT3→miR-197→IL-22R1 negative feedback loop was identified. Dual hepatoprotective/hepatotoxic roles were dissected by chronic versus acute IL-22 exposure affecting CYP2E1 via HNF-1α.","evidence":"ChIP for STAT3 at Il-18 and miR-197 promoters; organoid and KO epistasis (IL-22/IL-18); DOT1L expression with stemness gene assays; liver-specific STAT3 KO and CYP2E1 KO in IL-22 transgenic mice; IL-21-driven chromatin remodeling at il22 locus","pmids":["24796415","24816405","35169117","25208211","25063867"],"confidence":"High","gaps":["Whether IL-22→IL-18 circuit operates in tissues beyond intestinal epithelium is unknown","Quantitative dynamics of the miR-197 feedback loop in vivo were not established","Threshold dose/duration distinguishing protective from oncogenic STAT3 signaling remains undefined"]},{"year":2015,"claim":"Tyk2 was established as the essential kinase transducing IL-22 signals in intestinal epithelial cells: IEC-specific Tyk2 KO reduced STAT3 phosphorylation and worsened colitis, which could be rescued by high-dose IL-22-Fc. Separately, hepatic IL-22 signaling was shown to induce C3 complement for bacterial opsonization during pneumonia.","evidence":"Conditional IEC-specific Tyk2 KO with Citrobacter rodentium colitis; hepatic-specific IL-22Ra1 KO with S. pneumoniae infection and C3 assays","pmids":["26432894","27456484"],"confidence":"High","gaps":["Whether JAK1 is equally required in IECs was not tested in conditional models","Whether C3 induction is STAT3-dependent was not directly confirmed"]},{"year":2016,"claim":"IL-22BP isoform biology was resolved: IL-22BPi2 is the principal secreted antagonist while IL-22BPi1 is retained intracellularly; TNF and TLR2/retinoic acid regulate isoform expression, establishing IL-22BP as a rheostat for IL-22/STAT3 signaling.","evidence":"Isoform-specific constructs, secretion assays, IL-22 STAT3 reporter assays, TLR2 and retinoic acid stimulation of myeloid cells","pmids":["27678220"],"confidence":"High","gaps":["Structural basis for differential IL-22 binding affinity of isoforms was not resolved","In vivo isoform-specific functions in disease models were not tested"]},{"year":2017,"claim":"Two upstream regulatory pathways were defined: NF-κB p65 directly binds the IL22 promoter downstream of IL-18 in ILC3s, and PGE2 induces IL-22 via EP4/cAMP in T cells, broadening the map of signals controlling IL-22 production.","evidence":"ChIP for p65 at IL22 promoter, ILC3 proliferation assays; T cell-specific EP4 KO with in vivo hapten sensitization","pmids":["28842466","28583370"],"confidence":"High","gaps":["Whether p65 and AhR cooperate at the IL22 promoter was not addressed","cAMP effector (PKA vs EPAC) mediating EP4-driven IL-22 was not identified"]},{"year":2020,"claim":"Microbial metabolites (SCFAs) were linked to IL-22 production through GPR41, HDAC inhibition, and HIF1α direct binding to the Il22 promoter, connecting gut microbiota metabolism to mucosal IL-22 output. Separately, IL-22 was shown to be required for colitis in Il10−/− mice, shaping microbiome composition and epithelial hyperplasia.","evidence":"GPR41 KO, ChIP for HIF1α at Il22 promoter, histone modification assays; Il10−/−Il22−/− double KO genetic model with microbiome analysis","pmids":["32901017","31932715"],"confidence":"High","gaps":["Specific SCFAs (butyrate vs propionate) contributing most to HIF1α-driven IL-22 were not resolved","How IL-22 shapes microbiome composition mechanistically is unknown"]},{"year":2022,"claim":"The TNF→IL-22BP axis in dendritic cells was identified as a mechanism restricting IL-22 bioavailability during colitis, explaining how anti-TNF therapy restores mucosal healing through increased IL-22/STAT3 signaling.","evidence":"Humanized colitis model, TNF source dissection (membrane-bound vs soluble), IL-22BP induction in DCs, correlation in IBD patient sera","pmids":["35383266"],"confidence":"High","gaps":["Whether anti-TNF effects on IL-22BP are sufficient to explain mucosal healing versus other anti-TNF mechanisms was not formally tested","Isoform-specific regulation of IL-22BP by TNF was not fully characterized"]},{"year":2024,"claim":"IL-22 was shown to resolve metabolic-associated steatotic liver disease (MASLD) by acting on intestinal—not hepatic—epithelial cells to activate STAT3 and suppress WNT–β-catenin signaling, shrinking the absorptive enterocyte compartment and reversing macronutrient absorption, establishing a gut-liver metabolic axis for IL-22.","evidence":"IEC-specific receptor studies, STAT3 and WNT–β-catenin signaling analysis, intestinal morphometry in diet-induced MASLD mouse model","pmids":["39317186"],"confidence":"High","gaps":["Whether WNT–β-catenin suppression is a direct STAT3 transcriptional target or indirect was not fully resolved","Translatability of the IEC-centric mechanism to human MASLD therapy is untested"]},{"year":null,"claim":"Key unresolved questions include the structural basis for differential IL-22BP isoform antagonism, the precise dose and temporal thresholds separating IL-22's protective versus tumorigenic STAT3 signaling, how IL-22 remodels the gut microbiome, and whether the IL-22→STAT3→IL-18 epithelial circuit operates across all barrier tissues.","evidence":"","pmids":[],"confidence":"High","gaps":["Structural model of IL-22/IL-22BPi2 versus IL-22BPi3 interaction not available","No quantitative framework for protective versus oncogenic STAT3 thresholds","Mechanism of microbiome remodeling by IL-22 remains undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,2,3,8,10,11,23]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,21,33]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,3,5,12]}],"pathway":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,8,16,25,28,30]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,11,12,13,14,20,22,31,32,35]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,4,8,10,19,34]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,24,36]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[5,21,33]}],"complexes":[],"partners":["IL22RA1","IL10RB","IL22RA2","STAT3","JAK1","TYK2"],"other_free_text":[]},"mechanistic_narrative":"IL-22 is a secreted cytokine of the IL-10 family that acts on epithelial cells and hepatocytes to promote antimicrobial defense, tissue repair, and barrier integrity across mucosal and hepatic surfaces. It signals through a heterodimeric receptor of IL-22R1 and IL-10R2, activating JAK1/Tyk2 and downstream STAT1/STAT3/STAT5, ERK/JNK/p38 MAPK, and PI3K/Akt pathways, with STAT3 Ser727 phosphorylation required for maximal transcriptional output [PMID:12087100, PMID:26432894, PMID:10875937]. STAT3-dependent targets include acute-phase reactants, antimicrobial peptides, mucins, complement C3, antiapoptotic proteins (Bcl-2, Bcl-xL, Mcl-1), and an IL-22→STAT3→IL-18 epithelial circuit that expands intestinal stem cells; IL-22 also drives goblet cell hyperplasia, keratinocyte proliferation, and enterocyte compartment remodeling via WNT–β-catenin inhibition [PMID:15122762, PMID:35169117, PMID:24130494, PMID:39317186]. IL-22 bioavailability is regulated by soluble IL-22BP isoforms—with IL-22BPi2 functioning as the principal antagonist—and its production is controlled by AhR, NF-κB (via IL-18), STAT3 (via IL-21), HIF1α (via SCFAs/GPR41), and PGE2/EP4/cAMP signaling, while a STAT3-induced miR-197 negative feedback loop targets IL-22R1 to attenuate signaling [PMID:27678220, PMID:21600206, PMID:28842466, PMID:32901017, PMID:28583370, PMID:25208211]."},"prefetch_data":{"uniprot":{"accession":"Q9GZX6","full_name":"Interleukin-22","aliases":["Cytokine Zcyto18","IL-10-related T-cell-derived-inducible factor","IL-TIF"],"length_aa":179,"mass_kda":20.0,"function":"Cytokine that plays a critical role in modulating tissue responses during inflammation (PubMed:17204547). Plays an essential role in the regeneration of epithelial cells to maintain barrier function after injury and for the prevention of further tissue damage (PubMed:17204547). Unlike most of the cytokines, has no effect on immune cells. Signals through a heterodimeric receptor composed of two subunits, the specific receptor IL22RA1 which is present on non-immune cells in many organs and the shared subunit IL10RB (PubMed:10875937, PubMed:18599299). Ligation of IL22RA1 with IL22 induces activation of the tyrosine kinases JAK1 and TYK2, which in turn activates STAT3. In turn, promotes cell survival and proliferation through STAT3, ERK1/2 and PI3K/AKT pathways (PubMed:25793261, PubMed:31311100). Promotes phosphorylation of GSK3B at 'Ser-9' and CTTN (By similarity). Promotes epithelial cell spreading (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9GZX6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL22","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL22","total_profiled":1310},"omim":[{"mim_id":"621190","title":"MICRO RNA 617; MIR617","url":"https://www.omim.org/entry/621190"},{"mim_id":"616622","title":"IMMUNODEFICIENCY 42; IMD42","url":"https://www.omim.org/entry/616622"},{"mim_id":"616005","title":"IMMUNODEFICIENCY 36 WITH LYMPHOPROLIFERATION; IMD36","url":"https://www.omim.org/entry/616005"},{"mim_id":"615296","title":"INTERLEUKIN 1 FAMILY, MEMBER 10; IL1F10","url":"https://www.omim.org/entry/615296"},{"mim_id":"615207","title":"IMMUNODEFICIENCY 56; IMD56","url":"https://www.omim.org/entry/615207"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"urinary bladder","ntpm":1.4}],"url":"https://www.proteinatlas.org/search/IL22"},"hgnc":{"alias_symbol":["ILTIF","IL-21","zcyto18","IL-TIF","IL-D110","TIFa","TIFIL-23","IL-22","MGC79382","MGC79384"],"prev_symbol":[]},"alphafold":{"accession":"Q9GZX6","domains":[{"cath_id":"1.20.1250.10","chopping":"43-177","consensus_level":"high","plddt":97.1767,"start":43,"end":177}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9GZX6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9GZX6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9GZX6-F1-predicted_aligned_error_v6.png","plddt_mean":88.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL22","jax_strain_url":"https://www.jax.org/strain/search?query=IL22"},"sequence":{"accession":"Q9GZX6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9GZX6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9GZX6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9GZX6"}},"corpus_meta":[{"pmid":"17581588","id":"PMC_17581588","title":"IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells.","date":"2007","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/17581588","citation_count":1476,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32997932","id":"PMC_32997932","title":"The role of IL-22 in intestinal health and disease.","date":"2020","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32997932","citation_count":367,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21393631","id":"PMC_21393631","title":"Recent advances in IL-22 biology.","date":"2011","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21393631","citation_count":265,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17234735","id":"PMC_17234735","title":"The molecular basis of IL-21-mediated proliferation.","date":"2007","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/17234735","citation_count":256,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19088203","id":"PMC_19088203","title":"IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19088203","citation_count":229,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20445503","id":"PMC_20445503","title":"IL-22 defines a novel immune pathway of antifungal resistance.","date":"2010","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20445503","citation_count":219,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20691634","id":"PMC_20691634","title":"IL-17 and IL-22: siblings, not twins.","date":"2010","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20691634","citation_count":202,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29075900","id":"PMC_29075900","title":"Clinical importance of IL-22 cascade in IBD.","date":"2017","source":"Journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/29075900","citation_count":183,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24600453","id":"PMC_24600453","title":"Cytokine-Mediated Regulation of Plasma Cell Generation: IL-21 Takes Center Stage.","date":"2014","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24600453","citation_count":172,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12682241","id":"PMC_12682241","title":"IL-21 induces the apoptosis of resting and activated primary B cells.","date":"2003","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/12682241","citation_count":161,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24942687","id":"PMC_24942687","title":"Directing traffic: IL-17 and IL-22 coordinate pulmonary immune defense.","date":"2014","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/24942687","citation_count":158,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30773373","id":"PMC_30773373","title":"Clinical significance and immunobiology of IL-21 in autoimmunity.","date":"2019","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/30773373","citation_count":155,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30121291","id":"PMC_30121291","title":"Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab.","date":"2018","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30121291","citation_count":148,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19234181","id":"PMC_19234181","title":"IL-21 mediates suppressive effects via its induction of IL-10.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19234181","citation_count":147,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26966515","id":"PMC_26966515","title":"IL-21 Signaling in Immunity.","date":"2016","source":"F1000Research","url":"https://pubmed.ncbi.nlm.nih.gov/26966515","citation_count":144,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24796415","id":"PMC_24796415","title":"IL-21 induces IL-22 production in CD4+ T cells.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/24796415","citation_count":136,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17918200","id":"PMC_17918200","title":"IL-21 regulates experimental colitis by modulating the balance between Treg and Th17 cells.","date":"2007","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17918200","citation_count":136,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23746568","id":"PMC_23746568","title":"The role of IL-22 and Th22 cells in human skin diseases.","date":"2013","source":"Journal of dermatological science","url":"https://pubmed.ncbi.nlm.nih.gov/23746568","citation_count":135,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19201828","id":"PMC_19201828","title":"IL-21: an executor of B cell fate.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19201828","citation_count":125,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24130494","id":"PMC_24130494","title":"IL-22 mediates goblet cell hyperplasia and worm expulsion in intestinal helminth infection.","date":"2013","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/24130494","citation_count":122,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24459235","id":"PMC_24459235","title":"Toll-like receptor 4-induced IL-22 accelerates kidney regeneration.","date":"2014","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/24459235","citation_count":121,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16951332","id":"PMC_16951332","title":"IL-21 inhibits IFN-gamma production in developing Th1 cells through the repression of Eomesodermin expression.","date":"2006","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16951332","citation_count":117,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15728477","id":"PMC_15728477","title":"Differential effects of IL-21 during initiation and progression of autoimmunity against neuroantigen.","date":"2005","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/15728477","citation_count":110,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22359410","id":"PMC_22359410","title":"Healing of intestinal inflammation by IL-22.","date":"2012","source":"Inflammatory bowel diseases","url":"https://pubmed.ncbi.nlm.nih.gov/22359410","citation_count":108,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26170288","id":"PMC_26170288","title":"Opposing roles of STAT1 and STAT3 in IL-21 function in CD4+ T cells.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26170288","citation_count":107,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20220096","id":"PMC_20220096","title":"Redundant and pathogenic roles for IL-22 in mycobacterial, protozoan, and helminth infections.","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/20220096","citation_count":107,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20421880","id":"PMC_20421880","title":"Regulation of human Th9 differentiation by type I interferons and IL-21.","date":"2010","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20421880","citation_count":104,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15120651","id":"PMC_15120651","title":"IL-22, a Th1 cytokine that targets the pancreas and select other peripheral tissues.","date":"2004","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15120651","citation_count":103,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18209077","id":"PMC_18209077","title":"Autocrine regulation of IL-21 production in human T lymphocytes.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18209077","citation_count":99,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21106435","id":"PMC_21106435","title":"Distinct roles of IL-22 in human psoriasis and inflammatory bowel disease.","date":"2010","source":"Cytokine & growth factor reviews","url":"https://pubmed.ncbi.nlm.nih.gov/21106435","citation_count":96,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24616379","id":"PMC_24616379","title":"T cell-derived interleukin (IL)-21 promotes brain injury following stroke in mice.","date":"2014","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24616379","citation_count":95,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25586558","id":"PMC_25586558","title":"Interleukin (IL)-21 promotes intestinal IgA response to microbiota.","date":"2015","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25586558","citation_count":93,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24058193","id":"PMC_24058193","title":"IL-21-producing Th cells in immunity and autoimmunity.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24058193","citation_count":86,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22048239","id":"PMC_22048239","title":"IL-22, but not IL-17, dominant environment in cutaneous T-cell lymphoma.","date":"2011","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/22048239","citation_count":85,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35169117","id":"PMC_35169117","title":"IL-22 initiates an IL-18-dependent epithelial response circuit to enforce intestinal host defence.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35169117","citation_count":84,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31182797","id":"PMC_31182797","title":"IFN-I and IL-22 mediate protective effects of intestinal viral infection.","date":"2019","source":"Nature microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31182797","citation_count":84,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28842466","id":"PMC_28842466","title":"IL-18 Drives ILC3 Proliferation and Promotes IL-22 Production via NF-κB.","date":"2017","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/28842466","citation_count":82,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25467639","id":"PMC_25467639","title":"IL-22, cell regeneration and autoimmunity.","date":"2014","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/25467639","citation_count":73,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34224936","id":"PMC_34224936","title":"New developments implicating IL-21 in autoimmune disease.","date":"2021","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/34224936","citation_count":70,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17918202","id":"PMC_17918202","title":"Overexpression of IL-21 promotes massive CD8+ memory T cell accumulation.","date":"2007","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17918202","citation_count":70,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30364840","id":"PMC_30364840","title":"IL22 Inhibits Epithelial Stem Cell Expansion in an Ileal Organoid Model.","date":"2018","source":"Cellular and molecular gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/30364840","citation_count":69,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22785229","id":"PMC_22785229","title":"IL-15 positively regulates IL-21 production in celiac disease mucosa.","date":"2012","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22785229","citation_count":68,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17554014","id":"PMC_17554014","title":"IL-21 promotes T lymphocyte survival by activating the phosphatidylinositol-3 kinase signaling cascade.","date":"2007","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/17554014","citation_count":65,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23696736","id":"PMC_23696736","title":"IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection.","date":"2013","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/23696736","citation_count":64,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30684548","id":"PMC_30684548","title":"IL-17 and IL-22 Promote Keratinocyte Stemness in the Germinative Compartment in Psoriasis.","date":"2019","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/30684548","citation_count":63,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25801685","id":"PMC_25801685","title":"Advances in IL-21 biology - enhancing our understanding of human disease.","date":"2015","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25801685","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31932715","id":"PMC_31932715","title":"The development of colitis in Il10-/- mice is dependent on IL-22.","date":"2020","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31932715","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12700595","id":"PMC_12700595","title":"Cloning and characterization of mouse IL-22 binding protein.","date":"2003","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/12700595","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27435400","id":"PMC_27435400","title":"IL-21 Enhances Natural Killer Cell Response to Cetuximab-Coated Pancreatic Tumor Cells.","date":"2016","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/27435400","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25063867","id":"PMC_25063867","title":"Acute and chronic effects of IL-22 on acetaminophen-induced liver injury.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/25063867","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28583370","id":"PMC_28583370","title":"Prostaglandin E2 stimulates adaptive IL-22 production and promotes allergic contact dermatitis.","date":"2017","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28583370","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15201862","id":"PMC_15201862","title":"Cloning of murine IL-22 receptor alpha 2 and comparison with its human counterpart.","date":"2004","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/15201862","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19845910","id":"PMC_19845910","title":"IL-21: roles in immunopathology and cancer therapy.","date":"2009","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/19845910","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35316548","id":"PMC_35316548","title":"Role of IL-22 in homeostasis and diseases of the skin.","date":"2022","source":"APMIS : acta pathologica, microbiologica, et immunologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/35316548","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30111631","id":"PMC_30111631","title":"IL-21 Selectively Protects CD62L+ NKT Cells and Enhances Their Effector Functions for Adoptive Immunotherapy.","date":"2018","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/30111631","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26497621","id":"PMC_26497621","title":"Pathogen Resistance Mediated by IL-22 Signaling at the Epithelial-Microbiota Interface.","date":"2015","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26497621","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25208211","id":"PMC_25208211","title":"The crosstalk between IL-22 signaling and miR-197 in human keratinocytes.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25208211","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27456484","id":"PMC_27456484","title":"Critical Role of IL-22/IL22-RA1 Signaling in Pneumococcal Pneumonia.","date":"2016","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/27456484","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21593413","id":"PMC_21593413","title":"Key role for IL-21 in experimental autoimmune uveitis.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21593413","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28456711","id":"PMC_28456711","title":"Paeoniflorin suppressed IL-22 via p38 MAPK pathway and exerts anti-psoriatic effect.","date":"2017","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28456711","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26432894","id":"PMC_26432894","title":"Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/26432894","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35801309","id":"PMC_35801309","title":"IL-21 has a critical role in establishing germinal centers by amplifying early B cell proliferation.","date":"2022","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/35801309","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18773086","id":"PMC_18773086","title":"IL-21 limits peripheral lymphocyte numbers through T cell homeostatic mechanisms.","date":"2008","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/18773086","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18056403","id":"PMC_18056403","title":"IL-21 induces inhibitor of differentiation 2 and leads to complete abrogation of anaphylaxis in mice.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18056403","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11267886","id":"PMC_11267886","title":"Cytokines: IL-21 joins the gamma(c)-dependent network?","date":"2001","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/11267886","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31964625","id":"PMC_31964625","title":"IL6 Induces an IL22+ CD8+ T-cell Subset with Potent Antitumor Function.","date":"2020","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/31964625","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26130064","id":"PMC_26130064","title":"IL10R2 Overexpression Promotes IL22/STAT3 Signaling in Colorectal Carcinogenesis.","date":"2015","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/26130064","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24390134","id":"PMC_24390134","title":"Genetic variants of the IL22 promoter associate to onset of psoriasis before puberty and increased IL-22 production in T cells.","date":"2013","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/24390134","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27699266","id":"PMC_27699266","title":"Cyclosporine A immunosuppression drives catastrophic squamous cell carcinoma through IL-22.","date":"2016","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/27699266","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21441456","id":"PMC_21441456","title":"IL-21 promotes skin recruitment of CD4(+) cells and drives IFN-γ-dependent epidermal hyperplasia.","date":"2011","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21441456","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39317186","id":"PMC_39317186","title":"IL-22 resolves MASLD via enterocyte STAT3 restoration of diet-perturbed intestinal homeostasis.","date":"2024","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/39317186","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27055194","id":"PMC_27055194","title":"IL-22 Restrains Tapeworm-Mediated Protection against Experimental Colitis via Regulation of IL-25 Expression.","date":"2016","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/27055194","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25584898","id":"PMC_25584898","title":"A pathogenetic role for IL-21 in primary Sjögren syndrome.","date":"2015","source":"Nature reviews. Rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/25584898","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29713472","id":"PMC_29713472","title":"The role of IL-22 in the resolution of sterile and nonsterile inflammation.","date":"2018","source":"Clinical & translational immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29713472","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25495679","id":"PMC_25495679","title":"Increased IL-21 expression in chronic rhinosinusitis with nasalpolyps.","date":"2015","source":"Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25495679","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17447063","id":"PMC_17447063","title":"Role of IL-21 in immune-regulation and tumor immunotherapy.","date":"2007","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/17447063","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29296543","id":"PMC_29296543","title":"IL-21 promotes the development of a CD73-positive Vγ9Vδ2 T cell regulatory population.","date":"2017","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/29296543","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23172754","id":"PMC_23172754","title":"Implication of IL-2/IL-21 region in systemic sclerosis genetic susceptibility.","date":"2012","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/23172754","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31867283","id":"PMC_31867283","title":"Interleukin (IL)-21 in Inflammation and Immunity During Parasitic Diseases.","date":"2019","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31867283","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35383266","id":"PMC_35383266","title":"TNF hampers intestinal tissue repair in colitis by restricting IL-22 bioavailability.","date":"2022","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35383266","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24756111","id":"PMC_24756111","title":"Exploring the IL-21-STAT3 axis as therapeutic target for Sézary syndrome.","date":"2014","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/24756111","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24744495","id":"PMC_24744495","title":"Salivary IL-21 and IgA responses to a competitive match in elite basketball players.","date":"2013","source":"Biology of sport","url":"https://pubmed.ncbi.nlm.nih.gov/24744495","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23041403","id":"PMC_23041403","title":"Cerebrospinal fluid IL-21 levels in Neuromyelitis Optica and multiple sclerosis.","date":"2012","source":"The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques","url":"https://pubmed.ncbi.nlm.nih.gov/23041403","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27678220","id":"PMC_27678220","title":"Human IL-22 binding protein isoforms act as a rheostat for IL-22 signaling.","date":"2016","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/27678220","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23708911","id":"PMC_23708911","title":"Serum IL-21 levels decrease with glucocorticoid treatment in myasthenia gravis.","date":"2013","source":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/23708911","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32945375","id":"PMC_32945375","title":"Evaluation of the effects of IL‑22 on the proliferation and differentiation of keratinocytes in vitro.","date":"2020","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/32945375","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36839448","id":"PMC_36839448","title":"Current Knowledge of Th22 Cell and IL-22 Functions in Infectious Diseases.","date":"2023","source":"Pathogens (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36839448","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27400126","id":"PMC_27400126","title":"Natural allelic variation of the IL-21 receptor modulates ischemic stroke infarct volume.","date":"2016","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/27400126","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27067007","id":"PMC_27067007","title":"Dynamic Long-Range Chromatin Interaction Controls Expression of IL-21 in CD4+ T Cells.","date":"2016","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/27067007","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18556671","id":"PMC_18556671","title":"IL-21 promotes survival and maintains a naive phenotype in human CD4+ T lymphocytes.","date":"2008","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18556671","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30156011","id":"PMC_30156011","title":"IL-22 sustains epithelial integrity in progressive kidney remodeling and fibrosis.","date":"2018","source":"Physiological reports","url":"https://pubmed.ncbi.nlm.nih.gov/30156011","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29849593","id":"PMC_29849593","title":"Evaluating IL-21 as a Potential Therapeutic Target in Crohn's Disease.","date":"2018","source":"Gastroenterology research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/29849593","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32477345","id":"PMC_32477345","title":"IL-22 Paucity in APECED Is Associated With Mucosal and Microbial Alterations in Oral Cavity.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32477345","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21175418","id":"PMC_21175418","title":"IL-21 is an immune activator that also mediates suppression via IL-10.","date":"2010","source":"Critical reviews in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21175418","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21824785","id":"PMC_21824785","title":"The role of IL-21 in hematological malignancies.","date":"2011","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/21824785","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29131072","id":"PMC_29131072","title":"IL-21 Is Increased in Nasal Polyposis and after Stimulation with Staphylococcus aureus Enterotoxin B.","date":"2017","source":"International archives of allergy and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29131072","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23960240","id":"PMC_23960240","title":"The cellular source and target of IL-21 in K/BxN autoimmune arthritis.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23960240","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22250707","id":"PMC_22250707","title":"Psoriasis, from pathogenesis to therapeutic strategies: IL-21 as a novel potential therapeutic target.","date":"2012","source":"Current pharmaceutical biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/22250707","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32060889","id":"PMC_32060889","title":"IL-21 Signaling in the Tumor Microenvironment.","date":"2020","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/32060889","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18220949","id":"PMC_18220949","title":"Interleukin-21 (IL-21) controls inflammatory pathways in the gut.","date":"2007","source":"Endocrine, metabolic & immune disorders drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/18220949","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23128233","id":"PMC_23128233","title":"Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.","date":"2012","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23128233","citation_count":3725,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18978771","id":"PMC_18978771","title":"A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity.","date":"2008","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/18978771","citation_count":1061,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18264110","id":"PMC_18264110","title":"IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia.","date":"2008","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18264110","citation_count":962,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32352535","id":"PMC_32352535","title":"COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options.","date":"2020","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/32352535","citation_count":943,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32901017","id":"PMC_32901017","title":"Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32901017","citation_count":826,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19920355","id":"PMC_19920355","title":"Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling.","date":"2009","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/19920355","citation_count":807,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25706098","id":"PMC_25706098","title":"Interleukin-22: immunobiology and pathology.","date":"2015","source":"Annual review of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25706098","citation_count":730,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21600206","id":"PMC_21600206","title":"Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract.","date":"2011","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/21600206","citation_count":549,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19481975","id":"PMC_19481975","title":"Anti-inflammatory and pro-inflammatory roles of TGF-beta, IL-10, and IL-22 in immunity and autoimmunity.","date":"2009","source":"Current opinion in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/19481975","citation_count":526,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15122762","id":"PMC_15122762","title":"Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation.","date":"2004","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/15122762","citation_count":497,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20032993","id":"PMC_20032993","title":"Circulating Th17, Th22, and Th1 cells are increased in psoriasis.","date":"2009","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/20032993","citation_count":495,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16537974","id":"PMC_16537974","title":"IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration.","date":"2006","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16537974","citation_count":472,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10875937","id":"PMC_10875937","title":"Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10875937","citation_count":441,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19479869","id":"PMC_19479869","title":"Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis.","date":"2009","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/19479869","citation_count":437,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12087100","id":"PMC_12087100","title":"Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12087100","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16143135","id":"PMC_16143135","title":"Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts.","date":"2005","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/16143135","citation_count":400,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10657629","id":"PMC_10657629","title":"Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9.","date":"2000","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10657629","citation_count":399,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23405899","id":"PMC_23405899","title":"IL-22, not simply a Th17 cytokine.","date":"2013","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/23405899","citation_count":371,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19122664","id":"PMC_19122664","title":"Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study.","date":"2009","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19122664","citation_count":336,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25024136","id":"PMC_25024136","title":"CX₃CR1⁺ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22.","date":"2014","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25024136","citation_count":334,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11035029","id":"PMC_11035029","title":"Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rbeta ) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11035029","citation_count":330,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24610014","id":"PMC_24610014","title":"Epidermal Th22 and Tc17 cells form a localized disease memory in clinically healed psoriasis.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24610014","citation_count":329,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24816405","id":"PMC_24816405","title":"IL-22(+)CD4(+) T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L.","date":"2014","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/24816405","citation_count":324,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10954742","id":"PMC_10954742","title":"Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor.","date":"2000","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10954742","citation_count":292,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12975309","id":"PMC_12975309","title":"The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.","date":"2003","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/12975309","citation_count":285,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21124836","id":"PMC_21124836","title":"Overrepresentation of IL-17A and IL-22 producing CD8 T cells in lesional skin suggests their involvement in the pathogenesis of psoriasis.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21124836","citation_count":262,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21674558","id":"PMC_21674558","title":"Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3.","date":"2011","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/21674558","citation_count":259,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15765404","id":"PMC_15765404","title":"Interleukin-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn's disease.","date":"2005","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/15765404","citation_count":243,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45557,"output_tokens":6357,"usd":0.116013},"stage2":{"model":"claude-opus-4-6","input_tokens":10003,"output_tokens":4287,"usd":0.235785},"total_usd":0.80218,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":60690,"output_tokens":10561,"usd":0.170242},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":14412,"output_tokens":4588,"usd":0.28014}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-22 signals through a two-component receptor comprising IL-22R1 and CRF2-4/IL-10Rβ; tissue tropism is dictated by the restricted expression of IL-22R1, with highest expression in pancreatic acinar cells and lower but functional expression in skin, colon, liver, and kidney.\",\n      \"method\": \"receptor characterization, expression analysis\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — receptor complex identified and expression pattern characterized, moderate mechanistic detail, single review/characterization paper\",\n      \"pmids\": [\"15120651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mouse IL-22 binding protein (mIL-22BP) binds to mouse and human IL-22 and neutralizes STAT3 activation induced by both cytokines in hepatoma cell lines; mIL-22BP can be upregulated by LPS in monocytes and blocks IL-22-induced reactive oxygen species production in B cells.\",\n      \"method\": \"RT-PCR cloning, binding assay, STAT3 phosphorylation assay, ROS assay\",\n      \"journal\": \"Genes and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional assays (STAT3 neutralization, ROS blockade) with recombinant protein in cell lines\",\n      \"pmids\": [\"12700595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mouse and rat IL-22Rα2 (IL-22 binding protein) exists only as a soluble receptor lacking transmembrane and intracellular domains; its mRNA expression is limited in tissue distribution and is differentially modulated during systemic inflammation in spleen, thymus, and lymph node.\",\n      \"method\": \"Genomic cloning, sequence analysis, quantitative expression analysis in vivo\",\n      \"journal\": \"Genes and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — structural characterization combined with in vivo expression modulation data\",\n      \"pmids\": [\"15201862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-22 signals through a heterodimeric receptor (IL-22RA1/IL-10R2) and activates the STAT3 signaling pathway; IL-10 and IL-22 both activate STAT3, but IL-22 is dispensable for immunity to Toxoplasma gondii and Mycobacterium avium via i.p./i.v. routes, while playing a pathogenic role in intestinal toxoplasmosis via the oral route.\",\n      \"method\": \"IL-22-/- mice, neutralizing antibodies, cytokine/pathway analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout and antibody neutralization with defined phenotypic readouts, multiple infection models\",\n      \"pmids\": [\"20220096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL-22 directly induces goblet cell hyperplasia and expression of goblet cell markers including mucins in intestinal epithelial cells; IL-22-deficient mice show impaired worm expulsion and reduced goblet cell hyperplasia in helminth infection models (N. brasiliensis and T. muris).\",\n      \"method\": \"IL-22-/- mice, ex vivo and in vitro epithelial cell stimulation, goblet cell marker quantification\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with two independent infection models, confirmed by direct in vitro stimulation of epithelial cells\",\n      \"pmids\": [\"24130494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-22-mediated protection against acetaminophen-induced hepatotoxicity is dependent on STAT3 activation in hepatocytes, as IL-22 fails to protect liver-specific STAT3 knockout mice. Chronic constitutive IL-22 overexpression increases Cyp2E1 and Cyp1A2 via HNF-1α, exacerbating hepatotoxicity in an Cyp2E1-dependent manner.\",\n      \"method\": \"Liver-specific STAT3 KO mice, IL-22 transgenic mice, adenoviral IL-22 overexpression, Cyp2E1 KO, western blot\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple genetic models (STAT3 KO, Cyp2E1 KO, IL-22 TG), multiple orthogonal approaches\",\n      \"pmids\": [\"25063867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TLR4 signaling in interstitial mononuclear cells (dendritic cells and macrophages) drives IL-22 secretion in response to necrotic tubular cell-derived danger signals, and secreted IL-22 acts on tubular epithelial cells (which exclusively express IL-22 receptor) to accelerate regeneration after acute kidney injury.\",\n      \"method\": \"In vitro screening, IL-22 deficiency/blockade in mice, cell-depletion experiments, IL-22 reconstitution, TLR4 blockade\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches including KO, blockade, cell depletion, and rescue with recombinant IL-22\",\n      \"pmids\": [\"24459235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-21 induces IL-22 production in CD4+ T cells via STAT3 activation, which controls the epigenetic status of the il22 promoter and its interaction with the aryl hydrocarbon receptor (AhR); IL-21 and AhR signaling together control IL-22 production and development of colitis in ILC-deficient mice.\",\n      \"method\": \"In vitro CD4+ T cell stimulation, STAT3 ChIP, AhR inhibition/knockout, colitis model in ILC-deficient mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP linking STAT3 to il22 promoter, AhR functional validation, in vivo colitis model, multiple orthogonal methods\",\n      \"pmids\": [\"24796415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-22 acts via the IL-22RA1/IL-10R2 receptor to activate STAT3 via tyrosine kinase 2 (Tyk2) in intestinal epithelial cells; Tyk2-deficient IECs show reduced p-STAT3 and reduced IL-22-STAT3 target gene expression, and IEC-specific Tyk2 deletion exacerbates colitis, rescuable by high-dose rIL-22-Fc.\",\n      \"method\": \"Tyk2 KO mice, conditional IEC-specific Tyk2 KO, primary IEC p-STAT3 assay, colitis model, C. rodentium infection model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — conditional KO with defined molecular readout (p-STAT3), rescued by recombinant cytokine, confirmed in two disease models\",\n      \"pmids\": [\"26432894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-22 signaling through hepatic IL-22RA1 induces hepatic C3 complement production, increases C3 opsonization on Streptococcus pneumoniae, and is critical for controlling pneumococcal lung burden; hepatic-specific IL-22RA1 deletion increases bacterial burdens, demonstrating that IL-22 acts on the liver to enhance systemic antibacterial immunity.\",\n      \"method\": \"Il22-/- mice, hepatic-specific Il22ra1 deletion, rIL-22 administration, C3 binding assay, bacterial burden quantification\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — organ-specific conditional KO, recombinant cytokine rescue, direct C3 opsonization assay\",\n      \"pmids\": [\"27456484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Human IL-22BP is expressed as three isoforms (IL-22BPi1, i2, i3) generated by alternative splicing; IL-22BPi2 most potently inhibits IL-22-driven STAT3 signaling and is induced by TLR2 signaling and retinoic acid in myeloid cells; IL-22BPi3 is more abundant under homeostatic conditions but less inhibitory; IL-22BPi1 is not secreted and cannot antagonize IL-22 signaling.\",\n      \"method\": \"Isoform expression analysis, functional STAT3 signaling assays, TLR2/retinoic acid stimulation of myeloid cells\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple isoforms functionally characterized with orthogonal methods (secretion, STAT3, gene induction), mechanistic dissection of isoform-specific roles\",\n      \"pmids\": [\"27678220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-18 induces IL-22 production in human ILC3s via NF-κB; p65 (NF-κB subunit) binds the proximal IL22 promoter and promotes transcriptional activity; IL-18 cooperates with IL-15 to drive ILC3 proliferation.\",\n      \"method\": \"NF-κB activation assay, p65 ChIP on IL22 promoter, ILC3 proliferation and cytokine assays, in situ localization of IL-18-expressing DCs near ILC3s in human tonsil\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP directly linking NF-κB to IL22 promoter, functional cytokine assays, in situ tissue validation\",\n      \"pmids\": [\"28842466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-22 promotes crypt immunity by inducing phospho-STAT3 binding to the Il-18 gene promoter in intestinal epithelial cells, upregulating IL-18 production; IL-18 in turn promotes organoid budding and Lgr5+ stem cell signature genes via Akt-Tcf4 signaling. In AIEC infection, IL-22 is epistatic to IL-18, as IL-22 administration fails to restore parameters in Il-18-/- mice, placing IL-22-STAT3 upstream of IL-18-mediated barrier defense.\",\n      \"method\": \"STAT3 ChIP on Il-18 promoter, intestinal organoid culture, Il-22-/- and Il-18-/- mice, AIEC infection model, epistasis experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP, organoid reconstitution, genetic epistasis in two KO strains, infection model\",\n      \"pmids\": [\"35169117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-22 activates STAT3 (phospho-STAT3) in intestinal epithelial cells and promotes epithelial cell regeneration; constitutive STAT3 activation by IL-22 stimulates epithelial cell regeneration and reinforces mucosal barrier integrity through stimulating antibacterial peptide and mucin expression.\",\n      \"method\": \"STAT3 signaling assays in epithelial cells, loss-of-function and gain-of-function approaches in colitis models\",\n      \"journal\": \"Journal of gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — summarized mechanistic findings from multiple studies reviewed, not a single primary discovery paper\",\n      \"pmids\": [\"29075900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-22 induces keratinocyte proliferation via STAT3 signaling and activates the MAPK signaling pathway (p-JNK, p-ERK, p-p38), inhibits differentiation via downregulation of C/EBPα; siRNA knockdown of C/EBPα recapitulates increased proliferation and reduced differentiation markers.\",\n      \"method\": \"In vitro keratinocyte stimulation with recombinant IL-22, western blot for MAPK phosphorylation, CCK-8 proliferation assay, C/EBPα siRNA knockdown\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro mechanistic pathway analysis with siRNA validation, but single lab, single cell type\",\n      \"pmids\": [\"32945375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-22 induces miR-197 expression in keratinocytes through phospho-STAT3 binding to sequences in the miR-197 promoter; miR-197 in turn directly targets IL22RA1 (IL-22 receptor subunit), creating a negative feedback loop that attenuates IL-22 signaling and keratinocyte proliferation.\",\n      \"method\": \"Luciferase reporter assay, ChIP for pSTAT3 at miR-197 promoter, miR-197 overexpression, 3'UTR reporter assay for IL22RA1\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP, reporter assay, miRNA overexpression with functional readout (proliferation/migration), direct target validation\",\n      \"pmids\": [\"25208211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IFN-I signaling acts on intestinal epithelial cells to increase CCR2-dependent macrophages and IL-22-producing ILC3s; these IL-22-producing cells promote pSTAT3 signaling in intestinal epithelial cells and protection from intestinal injury; IL-22 provides striking protection against lethal Citrobacter rodentium infection in neonates.\",\n      \"method\": \"Murine norovirus infection model, conditional cell depletions, IL-22 KO mice, intestinal injury model, pSTAT3 signaling readout\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with mechanistic pathway analysis, multiple infection models, but mechanistic details of IL-22 signaling itself are downstream of IFN-I/MNV pathway focus\",\n      \"pmids\": [\"31182797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-22 is required for development of colitis in Il10-/- mice: Il10-/-Il22-/- double knockout mice do not develop colitis despite high Th17 cells and colitogenic Helicobacter spp.; IL-22 drives epithelia hyperplasia and antimicrobial gene expression (e.g., Reg3g) in this model, and its absence restores microbiome diversity.\",\n      \"method\": \"Double KO mice (Il10-/-Il22-/-), histology, antimicrobial gene expression, microbiome sequencing, Th17 cell analysis\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean double-knockout genetic epistasis with defined phenotypic (histological, molecular, microbial) readouts\",\n      \"pmids\": [\"31932715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"High IL-22 levels inhibit intestinal stem cell (ISC) expansion in ileal organoids: IL-22 reduces ISC biomarker expression and self-renewal pathway activity (including Wnt/Notch); IL22ra1 is expressed on only a subset of ISCs and transit-amplifying progenitors; in vivo chronic IL-22 overexpression increases TA progenitor but not ISC numbers.\",\n      \"method\": \"Ileal organoid culture with recombinant IL-22, single-cell RNA-seq for IL22ra1 expression, IL-22 transgenic mouse, immunostaining and serial passaging ISC assays\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — organoid functional assay, in vivo transgenic model, single-cell RNA-seq, multiple orthogonal methods\",\n      \"pmids\": [\"30364840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TNF induces expression of soluble IL-22 antagonist IL-22BP (IL-22Rα2/IL-22Ra2) in colonic dendritic cells (via soluble TNF from epithelial cells), thereby reducing IL-22 bioavailability and abrogating IL-22/STAT3-mediated mucosal repair during colitis; anti-TNF therapy reverses this by increasing IL-22 availability.\",\n      \"method\": \"Humanized colitis model, IL-22BP induction assay in DCs, pSTAT3 readout, correlation of IL-22BP and TNF in IBD patient sera\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway dissection with defined cell types and molecular readouts, but partly correlative in human samples\",\n      \"pmids\": [\"35383266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-22 acts through its epithelial receptor (IEC-expressed IL-22RA1, not hepatocyte receptor) to activate STAT3 and inhibit WNT-β-catenin signaling in intestinal epithelial cells, shrinking the absorptive enterocyte compartment and thereby reducing macronutrient absorption and resolving MASLD (metabolic dysfunction-associated steatotic liver disease).\",\n      \"method\": \"Recombinant IL-22 administration, conditional/cell-specific receptor KO, STAT3 and WNT-β-catenin pathway analysis, intestinal organoids, MASLD mouse model\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-specific KO (IEC vs hepatocyte), pathway analysis (STAT3/WNT), functional metabolic readout in MASLD model\",\n      \"pmids\": [\"39317186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Prostaglandin E2 (PGE2) induces IL-22 production from T cells through EP2 and EP4 receptors via cyclic AMP signaling; selective T-cell deletion of EP4 prevents hapten-induced IL-22 production in vivo and limits atopic-like skin inflammation in an oxazolone ACD model.\",\n      \"method\": \"T-cell culture, EP receptor antagonists/agonists, T-cell specific EP4 KO mice, oxazolone skin inflammation model, cAMP signaling assays\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional T-cell-specific KO, receptor pharmacology, in vivo disease model, defined signaling pathway\",\n      \"pmids\": [\"28583370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-22 acts on intestinal epithelial cells via the IL-22RA1-IL-10R2 receptor complex to induce changes in gene expression affecting epithelial barrier integrity, including mucus layer modifications, tight junction fortification, and production of bactericidal compounds (e.g., antimicrobial peptides), thereby mediating colonization resistance to intestinal pathogens.\",\n      \"method\": \"Review of mechanistic studies; receptor complex signaling pathway characterization\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — review synthesizing mechanistic findings from multiple primary papers, not a primary discovery paper itself\",\n      \"pmids\": [\"26497621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-22 defines a first-line antifungal defense pathway that is upregulated under Th1 deficiency and reciprocally regulated with Th1 immunity; IL-22 mediates protection in IL-17RA-deficient mice against Candida albicans, controlling yeast growth and maintaining epithelial integrity independently of acquired Th1-type immunity.\",\n      \"method\": \"IL-17RA-/- mice, IL-22 neutralization, Candida albicans infection model, cytokine/immune response analysis\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO and neutralization in infection model, epistasis between IL-22 and IL-17/Th1 pathways\",\n      \"pmids\": [\"20445503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL-22 promotes IL-22-induced keratinocyte proliferation and epidermal hyperplasia, inhibits terminal differentiation of keratinocytes, and promotes production of antimicrobial proteins in skin.\",\n      \"method\": \"Primary keratinocyte culture, in vitro IL-22 stimulation assays, gene expression analysis\",\n      \"journal\": \"Journal of dermatological science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — review paper but describes established in vitro mechanistic findings that are foundational to IL-22 skin biology\",\n      \"pmids\": [\"23746568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL10R2 overexpression in colorectal carcinoma enhances IL-22/STAT3 signaling: IL-22 (but not IL-10) phosphorylates STAT3 along with AKT and ERK in HT29 cells, and IL10R2 transient overexpression increases proliferation upon IL-22 stimulation, indicating a specific role for the IL-22/IL10R2/STAT3 axis in colorectal carcinogenesis.\",\n      \"method\": \"IL10R2 transient overexpression in HT29 cells, STAT3/AKT/ERK phosphorylation assays, proliferation assays, matched tumor/normal tissue expression analysis\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic cell-based experiments with recombinant cytokine and signaling pathway validation\",\n      \"pmids\": [\"26130064\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-22 is a cytokine that signals exclusively through a heterodimeric receptor complex (IL-22RA1/IL-10R2) expressed on non-hematopoietic cells (epithelial cells, hepatocytes, keratinocytes), activating JAK/STAT3 (primarily via Tyk2 in intestinal epithelium), MAPK, and PI3K/AKT pathways to drive epithelial proliferation, barrier integrity, antimicrobial peptide production, and tissue repair; its signaling is fine-tuned by a soluble decoy receptor IL-22BP (IL-22RA2, with three human isoforms of differential inhibitory capacity), a negative feedback loop via STAT3-induced miR-197 targeting IL22RA1, and an IL-22→pSTAT3→IL-18→Akt-Tcf4 epithelial relay circuit that governs stem cell expansion and barrier defense.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper, then extract discoveries only from KEEP papers.\n\n**Classification Notes:**\n- Papers about IL-21 (a different gene) → EXCLUDE (alias/symbol collision)\n- Papers about IL-22 → KEEP\n- The additional curated papers labeled IL22 gene2pubmed → check each\n\nMany papers in the corpus (especially PMID 17581588, 17234735, 19088203, 12682241, 24600453, 30773373, 19234181, 26966515, 24058193, 19201828, 21393631 [mixed], 20421880, 19234181, 18209077, 17918200, 16951332, 15728477, 26170288, 17918202, 17554014, 23696736, 24744495, 23041403, 25801685, 34224936, 18773086, 18056403, 11267886, 23960240, 22250707, 25584898, 21824785, 21175418, 29849593, 27400126, 27067007, 23172754, 19845910, 18220949, 29131072, 25495679, 17447063, 29296543, 32060889, 21441456, 21593413, 24616379, 35801309, 18556671) are about **IL-21**, not IL-22 → **EXCLUDE**.\n\nPapers clearly about IL-22 → **KEEP**.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"IL-22 (originally termed IL-TIF) was identified as a novel cytokine structurally related to IL-10; it signals through a two-component receptor complex consisting of CRF2-9 (IL-22R1) and IL-10R2 (CRF2-4), activating STAT1, STAT3, and STAT5 in responsive cell lines but not inhibiting LPS-induced proinflammatory cytokines in monocytes, distinguishing it functionally from IL-10.\",\n      \"method\": \"Receptor binding assays, STAT activation assays in cell lines, functional cytokine production assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original discovery paper with receptor identification and signaling characterization, replicated in multiple cell lines\",\n      \"pmids\": [\"10875937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Mouse IL-TIF (IL-22) was cloned and shown to be induced by IL-9 in T cells and mast cells; recombinant protein activated STAT1 and STAT3 in hepatoma cells and stimulated acute phase reactants (serum amyloid A, alpha1-antichymotrypsin, haptoglobin) in HepG2 hepatoma cells; anti-IL-10R2 antibody blocked IL-22-induced acute phase reactant induction, establishing IL-10R2 as a shared receptor chain.\",\n      \"method\": \"cDNA subtraction cloning, recombinant protein stimulation, Western blot for STAT activation, antibody blockade\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original cloning with functional characterization and receptor blocking experiments\",\n      \"pmids\": [\"10657629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The functional IL-22 receptor complex was identified as a heterodimer of the orphan CRF2-9 chain (IL-22R1) and IL-10R2; each chain can independently bind IL-22 but cooperative binding occurs with the complex; the CRF2-9 intracellular domain is responsible for STAT recruitment, and substitution with IFN-gammaR1 intracellular domain changes the STAT activation pattern.\",\n      \"method\": \"COS cell expression of receptor chains, hamster cell reconstitution, radiolabeled IL-22 cross-linking, intracellular domain swap experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — receptor reconstitution with domain swap mutagenesis confirming functional mechanism\",\n      \"pmids\": [\"11035029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Human IL-TIF (IL-22) was cloned; recombinant protein activated STAT1 and STAT3 in hepatoma cell lines and stimulated acute phase reactants; anti-IL-10R2 antibodies blocked IL-22-induced acute phase reactant induction, confirming IL-10R2 as a shared receptor chain for IL-10 and IL-22.\",\n      \"method\": \"cDNA cloning, STAT activation assays, ELISA for acute phase proteins, antibody neutralization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — human gene cloning with receptor blockade and functional characterization\",\n      \"pmids\": [\"10954742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IL-22 activates JAK1 and Tyk2 (but not JAK2), and phosphorylates STAT1, STAT3, and STAT5 on tyrosine residues in rat hepatoma H4IIE cells; additionally IL-22 activates all three major MAPK pathways (ERK1/2, JNK, p38); IL-22 also induces serine phosphorylation of STAT3 on Ser727 independently of MEK1/2, and a STAT3 S727A mutant shows reduced transactivation, establishing that Ser727 phosphorylation is required for maximum STAT3 transcriptional activity downstream of IL-22.\",\n      \"method\": \"Immunoblot with phospho-specific antibodies, kinase-specific inhibitors, STAT3 S727A mutant overexpression, transcriptional reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro signaling pathway dissection with mutagenesis and pharmacological inhibitors\",\n      \"pmids\": [\"12087100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mouse IL-22 binding protein (mIL-22BP) was cloned; it binds both mouse and human IL-22 and neutralizes STAT3 activation induced by IL-22 in human and rat hepatoma cell lines; mIL-22BP blocks IL-22-induced reactive oxygen species production in B cells; mIL-22BP expression is upregulated by LPS in mouse monocytes.\",\n      \"method\": \"Genomic library screening, RT-PCR, binding assays, STAT3 activation assays, ROS measurement\",\n      \"journal\": \"Genes and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — functional receptor characterization with binding and signaling neutralization assays\",\n      \"pmids\": [\"12700595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mouse and rat homologs of IL-22Rα2 (IL-22 binding protein) were identified; like human IL-22Rα2, they exist only as soluble receptors lacking transmembrane and intracellular domains; the murine gene is located between IFNGR1 and IL-20R1 genes (syntenic with human); IL-22Rα2 mRNA shows limited tissue distribution and differential modulation during systemic inflammation in spleen, thymus, and lymph node.\",\n      \"method\": \"Genomic sequence analysis, RT-PCR, quantitative expression analysis\",\n      \"journal\": \"Genes and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — structural and expression characterization without full functional reconstitution\",\n      \"pmids\": [\"15201862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-22 receptor (IL-22R1) expression is highly restricted, with highest expression in pancreatic acinar cells, and lower functional levels in skin, colon, liver, and kidney; IL-22 signals through a heterodimer of IL-22R1 and CRF2-4/IL-10Rb; IL-22 induces acute-phase-type responses resembling IL-6 activity.\",\n      \"method\": \"Expression analysis, receptor characterization, functional cytokine assays\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — receptor expression mapping with functional characterization\",\n      \"pmids\": [\"15120651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-22 is a survival factor for hepatocytes acting via STAT3 activation: IL-22 blockade worsened T cell-mediated hepatitis whereas recombinant IL-22 attenuated it; stable overexpression of IL-22 in HepG2 cells constitutively activated STAT3 and induced antiapoptotic proteins (Bcl-2, Bcl-xL, Mcl-1) and mitogenic proteins (c-myc, cyclin D1, CDK4); blocking STAT3 activation abolished IL-22's antiapoptotic and mitogenic actions.\",\n      \"method\": \"Neutralizing antibody in vivo, recombinant cytokine injection, stable overexpression, STAT3 inhibition, Western blot for downstream targets\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal approaches (in vivo neutralization, in vitro overexpression, STAT3 blockade) confirming the mechanism\",\n      \"pmids\": [\"15122762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IL-22 activates NF-κB and AP-1 within 1 hour in colonic subepithelial myofibroblasts (SEMFs) and induces expression of proinflammatory cytokines (IL-6, IL-8, IL-11, LIF) and matrix metalloproteinases; NF-κB and AP-1 blockade markedly reduced these effects; MAP kinase inhibitors (PD98059, SB202190) significantly reduced IL-22-induced cytokine secretion; IL-17 plus IL-22, or IL-19 plus IL-22, additively upregulated cytokine secretion.\",\n      \"method\": \"cDNA microarray, Northern blot, ELISA, EMSA for NF-κB/AP-1, pharmacological inhibitors\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple pathway inhibition experiments with mechanistic readouts\",\n      \"pmids\": [\"16143135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-22 binds to its receptor complex (IL-22R1 and IL-10R2) on intestinal epithelial cell (IEC) lines, activating STAT1/3, Akt, ERK1/2, and SAPK/JNK MAP kinases; IL-22 increased IEC proliferation and phosphatidylinositol 3-kinase (PI3K)-dependent IEC migration; TNF-α, IL-1β, and LPS upregulated IL-22R1 but not IL-10R2 expression; IL-22 induced TNF-α, IL-8, and human beta-defensin-2 expression in IECs.\",\n      \"method\": \"Western blot for signaling pathways, proliferation assay, PI3K inhibitor treatment, wounding/migration assay, RT-PCR\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — comprehensive signaling pathway mapping with PI3K inhibitor mechanistic confirmation\",\n      \"pmids\": [\"16537974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-22 mediates mucosal host defense against Klebsiella pneumoniae: IL-22 increased lung epithelial cell proliferation and transepithelial resistance to injury; both IL-22 and IL-17A regulated CXC chemokine and G-CSF production in the lung, but only IL-22 promoted epithelial barrier protection.\",\n      \"method\": \"Mouse infection model with IL-22 and IL-17A neutralization/KO, epithelial barrier assays, chemokine measurement\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic and antibody blockade with specific epithelial phenotypic readouts\",\n      \"pmids\": [\"18264110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A human NK cell subset (NK-22 cells) located in mucosa-associated lymphoid tissues is hard-wired to secrete IL-22, IL-26, and LIF; these cells are triggered by IL-23 exposure; NK-22-secreted cytokines stimulate epithelial cells to secrete IL-10, proliferate, and express mitogenic and anti-apoptotic molecules in vitro; NK-22 cells appear in mouse small intestine lamina propria during bacterial infection.\",\n      \"method\": \"Cell isolation and characterization, cytokine stimulation assays, in vitro epithelial cell co-culture, in vivo bacterial infection model\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods identifying a new cellular source and functional consequence of IL-22\",\n      \"pmids\": [\"18978771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Aryl hydrocarbon receptor (AhR) signaling upregulates IL-22 production and inhibits intestinal inflammation: AhR agonist (Ficz) reduced IFN-γ and upregulated IL-22 in intestinal lamina propria mononuclear cells from IBD patients; in vivo Ficz protected mice against TNBS-, DSS-, and T-cell-transfer-induced colitis with marked induction of IL-22; AhR antagonist reduced IL-22 and worsened colitis; neutralization of endogenous IL-22 disrupted the protective effect of Ficz, placing AhR upstream of IL-22 in this pathway.\",\n      \"method\": \"In vitro cytokine production assays, multiple in vivo colitis models with AhR agonist/antagonist, IL-22 neutralizing antibody epistasis experiment\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple models plus IL-22 neutralization epistasis establishing AhR→IL-22 pathway\",\n      \"pmids\": [\"21600206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL-22 directly induces goblet cell hyperplasia and expression of goblet cell markers including mucins in intestinal epithelial cells ex vivo and in vitro; IL-22-deficient mice show impaired worm expulsion and reduced goblet cell hyperplasia after Nippostrongylus brasiliensis or Trichuris muris infection despite normal type 2 cytokine production.\",\n      \"method\": \"IL-22 KO mouse infection model, ex vivo and in vitro epithelial stimulation, goblet cell marker quantification\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO combined with in vitro direct stimulation establishing IL-22 → goblet cell hyperplasia mechanism\",\n      \"pmids\": [\"24130494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-22 promotes intestinal epithelial cell regeneration after acute kidney injury (AKI) via TLR4 signaling: necrotic tubular cells and oxidative stress induced IL-22 secretion selectively through TLR4; IL-22 deficiency or blockade impaired post-ischemic tubular recovery; TLR4 blockade during healing phase suppressed IL-22 production and impaired kidney regeneration; IL-22 receptor is expressed exclusively by tubular epithelial cells while IL-22 is secreted by interstitial dendritic cells and macrophages.\",\n      \"method\": \"IL-22 KO mice, IL-22 blockade, TLR4 blockade, cell depletion/reconstitution experiments, in vitro tubular cell recovery assay\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and pharmacological interventions with rescue experiments establishing TLR4→IL-22→tubular repair pathway\",\n      \"pmids\": [\"24459235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-22-producing CD4+ T cells promote colorectal cancer stemness via STAT3 activation and induction of the histone methyltransferase DOT1L; IL-22-activated STAT3 drives DOT1L expression which induces core stem cell genes NANOG, SOX2, and Pou5F1, increasing cancer stemness; CCR6/CCL20 chemokine axis mediates migration of IL-22-producing CD4+ T cells into the colon cancer microenvironment.\",\n      \"method\": \"Patient tissue analysis, mouse colon cancer model, STAT3 activation assays, DOT1L expression analysis, stem cell gene expression, CCR6 KO experiments\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway from IL-22→STAT3→DOT1L→stemness genes established in vitro and in vivo\",\n      \"pmids\": [\"24816405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-22 protects mice from acetaminophen-induced liver injury (AILI) acutely through STAT3 activation (IL-22 failed to protect in liver-specific STAT3 KO mice); however, chronic constitutive IL-22 overexpression exacerbates AILI by upregulating CYP2E1 via elevated HNF-1α; CYP2E1 ablation but not hepatic STAT3 deletion abolished AILI enhancement in IL-22 transgenic mice.\",\n      \"method\": \"Liver-specific STAT3 KO, IL-22 transgenic mice, IL-22 adenovirus treatment, CYP2E1 KO, HNF-1α expression analysis\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple tissue-specific KO models with opposing temporal mechanisms genetically dissected\",\n      \"pmids\": [\"25063867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-21 induces IL-22 production by CD4+ T cells through STAT3, which controls the epigenetic status of the il22 promoter and its interaction with the aryl hydrocarbon receptor (AhR); IL-21 and AhR signaling in T cells cooperate to control IL-22 production and dextran sodium sulfate-induced colitis in ILC-deficient mice.\",\n      \"method\": \"In vitro T cell stimulation, STAT3 activation and chromatin analysis, AhR interaction assays, in vivo colitis model in ILC-deficient mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epigenetic mechanism with in vivo validation linking IL-21/STAT3/AhR to IL-22 production\",\n      \"pmids\": [\"24796415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Intestinal epithelial cell (IEC)-specific Tyrosine kinase 2 (Tyk2) transduces IL-22 signals to protect from acute colitis: Tyk2-deficient primary IECs show reduced STAT3 phosphorylation in response to IL-22; IEC-specific Tyk2 KO mice develop more severe colitis with less pSTAT3 in colon tissue and reduced IEC proliferation; disease can be alleviated by high-dose rIL-22-Fc, indicating Tyk2 deficiency is overcome by increased receptor engagement.\",\n      \"method\": \"Conditional Tyk2 KO mice, primary IEC stimulation with IL-22, pSTAT3 assays, colitis model with Citrobacter rodentium\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — IEC-specific conditional KO with mechanistic rescue establishing Tyk2 as IL-22 signal transducer\",\n      \"pmids\": [\"26432894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-22 signaling in the liver during pneumococcal pneumonia promotes host defense by increasing hepatic C3 complement expression; IL-22 administration increased C3 binding on S. pneumoniae surfaces (opsonization); mice with hepatic-specific deletion of IL-22Ra1 had higher bacterial burdens, establishing that IL-22 → hepatic C3 → bacterial opsonization is a key defense mechanism.\",\n      \"method\": \"Hepatic-specific IL-22Ra1 KO mice, recombinant IL-22 administration, C3 expression assays, opsonic killing assays\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO with mechanistic pathway identification through complement pathway\",\n      \"pmids\": [\"27456484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Human IL-22 binding protein (IL-22BP) exists in three isoforms generated by alternative splicing with distinct functions: IL-22BPi2 has greater inhibitory activity than IL-22BPi3; IL-22BPi1 is not secreted and fails to antagonize IL-22; IL-22BPi2 is selectively increased by TLR2 signaling and retinoic acid in myeloid cells; IL-22BPi2 more effectively blocks IL-22/IL-17 cooperative gene induction than IL-22BPi3, functioning as a rheostat for IL-22/STAT3 responses.\",\n      \"method\": \"Isoform-specific expression constructs, secretion assays, IL-22 STAT3 reporter assays, TLR2 and retinoic acid stimulation of myeloid cells\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — functional characterization of all three isoforms with mechanistic dissection of differential inhibitory activities\",\n      \"pmids\": [\"27678220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-18 drives ILC3 proliferation and IL-22 production via NF-κB: the NF-κB complex component p65 binds to the proximal region of the IL22 promoter and promotes transcriptional activity; IL-18 cooperates with IL-15 to induce human ILC3 proliferation and IL-22 production; CD11c+ dendritic cells expressing IL-18 are found in close proximity to ILC3s in human tonsils.\",\n      \"method\": \"NF-κB p65 ChIP assay at IL22 promoter, ILC3 proliferation assays, IL-22 production measurement, in situ proximity analysis in tonsil tissue\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP assay establishing direct p65 binding to IL22 promoter plus functional validation\",\n      \"pmids\": [\"28842466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-22 directly induces keratinocyte proliferation and epidermal hyperplasia, inhibits terminal differentiation, and promotes production of antimicrobial proteins in the skin; IL-22 and TNF-α act synergistically on keratinocytes in proinflammatory Th22 responses; wound healing in an in vitro injury model is exclusively dependent on IL-22 from Th22 supernatants.\",\n      \"method\": \"Primary keratinocyte cultures, Th22 cell supernatant stimulation, wound healing assay, neutralizing antibody experiments\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — specific IL-22 neutralization demonstrates exclusive role in wound healing mechanism\",\n      \"pmids\": [\"19920355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-22 promotes human hepatocellular carcinoma growth via STAT3 activation: IL-22 induces phosphorylation of STAT3 and upregulates downstream genes Bcl-2, Bcl-xL, CyclinD1, and VEGF in HCC cells; tumor formation was significantly decreased in IL-22 knockout mice in a diethylnitrosamine-induced HCC model.\",\n      \"method\": \"IL-22 KO mouse HCC model, STAT3 phosphorylation assays, downstream target gene expression, in vivo subrenal cotransplantation experiments\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — IL-22 KO in vivo model combined with STAT3 pathway characterization\",\n      \"pmids\": [\"21674558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-22 signals through pSTAT3 binding to the Il-18 gene promoter to induce epithelial IL-18 production, placing IL-22-STAT3 signaling upstream of IL-18-mediated intestinal barrier defense; in organoids, IL-22 primarily increases size and inhibits stem cell genes while IL-18 preferentially promotes organoid budding via Akt-Tcf4 signaling; systemic IL-18 corrects compromised T-cell IFNγ and Paneth cells in Il-22-/- mice during AIEC infection, but IL-22 fails to restore these in Il-18-/- mice.\",\n      \"method\": \"ChIP (pSTAT3 at Il-18 promoter), intestinal organoid culture, IL-22 and IL-18 KO mice, AIEC infection model, genetic epistasis experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP establishing direct STAT3 binding plus genetic epistasis placing IL-22 upstream of IL-18\",\n      \"pmids\": [\"35169117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"High IL-22 levels inhibit ileal intestinal stem cell (ISC) expansion in favor of transit-amplifying (TA) progenitor expansion; IL-22Ra1 is expressed on only a subset of ISCs and TA progenitors; IL-22 reduces ISC biomarker expression, self-renewal pathway activity, and ISC expansion without causing major differentiation defects; in vivo, chronic IL-22 overexpression (IL-22 transgenic mice) increases TA zone proliferative cells without increasing ISC numbers.\",\n      \"method\": \"Ileal mouse organoid screen, single-cell RNA sequencing for Il22ra1 expression, ISC serial passaging assay, IL-22 transgenic mouse analysis\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — organoid functional assays combined with in vivo transgenic model and single-cell receptor mapping\",\n      \"pmids\": [\"30364840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-22 inhibits keratinocyte terminal differentiation and reduces expression of C/EBPα; IL-22 induces phosphorylation of JNK, ERK, and p38 via the MAPK signaling pathway in keratinocytes; siRNA knockdown of C/EBPα phenocopies IL-22's proliferative effect, increasing keratinocyte proliferation and reducing cytokeratin 10 and involucrin expression.\",\n      \"method\": \"Keratinocyte stimulation with recombinant IL-22, Western blot for phospho-MAPK, qRT-PCR, CCK-8 proliferation assay, C/EBPα siRNA knockdown\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pharmacological pathway analysis plus siRNA confirming C/EBPα as mediator\",\n      \"pmids\": [\"32945375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-22 activates STAT3 in keratinocytes, and phosphorylated STAT3 binds to sequences in the putative miR-197 promoter inducing miR-197 expression; miR-197 overexpression inhibits IL-22-induced keratinocyte proliferation and migration; miR-197 directly targets IL-22RA1 (IL-22 receptor subunit), creating a negative feedback loop where IL-22 induces miR-197 which in turn downregulates IL-22 receptor and attenuates IL-22 signaling.\",\n      \"method\": \"Luciferase reporter assay, STAT3 ChIP at miR-197 promoter, miR-197 overexpression, migration assays, IL22RA1 3'UTR targeting validation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP for STAT3 binding plus functional validation of the feedback loop with receptor targeting\",\n      \"pmids\": [\"25208211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Prostaglandin E2 (PGE2) induces IL-22 production from T cells through EP2 and EP4 receptors via cyclic AMP signaling; selective deletion of EP4 in T cells prevents hapten-induced IL-22 production in vivo and limits atopic-like skin inflammation in the oxazolone-induced allergic contact dermatitis model.\",\n      \"method\": \"T-cell cultures with PGE2 and receptor-specific agonists/antagonists, T cell-specific EP4 KO mice, in vivo hapten sensitization model\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — T cell-specific KO with in vivo phenotypic readout establishing PGE2→EP4→cAMP→IL-22 pathway\",\n      \"pmids\": [\"28583370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Microbiota-derived short-chain fatty acids (SCFAs) promote IL-22 production by CD4+ T cells and ILCs through G-protein receptor 41 (GPR41) and HDAC inhibition; SCFAs upregulate IL-22 by promoting aryl hydrocarbon receptor (AhR) and HIF1α expression; HIF1α binds directly to the Il22 promoter, and SCFAs increase HIF1α binding through histone modification; mTOR and Stat3 differentially regulate AhR and HIF1α expression.\",\n      \"method\": \"GPR41 KO, HDAC inhibitor studies, ChIP for HIF1α at Il22 promoter, mTOR/STAT3 inhibition, histone modification assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP establishing direct HIF1α binding to Il22 promoter combined with multiple genetic and pharmacological approaches\",\n      \"pmids\": [\"32901017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-22 is required for the development of colitis in Il10-/- mice: Il10-/-Il22-/- double KO mice did not develop colitis despite retaining high levels of Th17 cells and colitogenic Helicobacter spp.; IL-22-driven IEC hyperplasia and Reg3g antimicrobial gene expression were reversed in double KO mice; IL-22 shaped the fecal microbiome diversity in Il10-/- mice.\",\n      \"method\": \"Il10-/-Il22-/- double KO genetic model, histology, antimicrobial gene expression, 16S microbiome analysis\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean double-KO genetic model revealing epistatic relationship between IL-10 and IL-22 in colitis\",\n      \"pmids\": [\"31932715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IFN-I acts on intestinal epithelial cells during murine norovirus infection to increase CCR2-dependent macrophages and IL-22-producing innate lymphoid cells; IL-22 then promotes pSTAT3 signaling in intestinal epithelial cells and protection from intestinal injury; MNV provides striking IL-22-dependent protection against Citrobacter rodentium lethal infection in neonates.\",\n      \"method\": \"MNV infection model, IFN-I signaling analysis, IL-22 KO mice, ILC characterization, STAT3 signaling assays\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — IL-22 KO genetic model with mechanistic pathway analysis in viral infection context\",\n      \"pmids\": [\"31182797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TNF induces IL-22Ra2 (IL-22BP, a soluble IL-22 antagonist) in colonic dendritic cells, thereby restricting IL-22 bioavailability and abrogating IL-22/STAT3-mediated mucosal repair during colitis; membrane-bound TNF from T cells perpetuates colonic inflammation while soluble TNF from epithelial cells specifically drives IL-22BP expression in colonic DCs; anti-TNF therapy increases IL-22 availability, explaining mucosal healing.\",\n      \"method\": \"Humanized colitis model, TNF source identification, IL-22BP induction assays in DCs, IL-22/STAT3 signaling readouts, correlation of IL-22BP with TNF in IBD patient sera\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection of TNF sources and IL-22BP induction with functional STAT3 signaling readouts\",\n      \"pmids\": [\"35383266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Recombinant IL-22 resolves MASLD by acting through its IEC receptor (not hepatocytes) to activate STAT3 and inhibit WNT-β-catenin signaling in intestinal epithelial cells, thereby shrinking the absorptive enterocyte compartment and reversing macronutrient absorption; this mechanism reversed hepatosteatosis, inflammation, fibrosis, and insulin resistance; obesogenic diets suppress IL-22 production by small intestine innate lymphocytes, causing STAT3 inhibition in IECs.\",\n      \"method\": \"Recombinant IL-22 treatment, IEC-specific receptor studies, STAT3 and WNT-β-catenin signaling analysis, intestinal morphometric analysis, diet-induced MASLD mouse model\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — receptor-specific pathway dissection (IEC vs hepatocyte) with mechanistic signaling readouts in disease model\",\n      \"pmids\": [\"39317186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-22 provides antifungal defense against Candida albicans independent of IL-17A/F, controlling yeast growth and contributing to epithelial integrity; IL-22 is upregulated under Th1-deficient conditions; in IL-17RA-deficient mice (where IL-17A contributes to susceptibility), IL-22 mediates protection against candidiasis.\",\n      \"method\": \"IL-17RA KO mice, IL-22 neutralization, Candida albicans infection model, epithelial integrity assays\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO and antibody neutralization models establishing IL-22's independent antifungal pathway\",\n      \"pmids\": [\"20445503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-22 and cyclosporine A (CSA) cooperate to promote squamous cell carcinoma (SCC): CSA drives T cell polarization toward IL-22-producing T22 cells and increases IL-22 receptor expression on SCC cells; IL-22 combined with CSA increased SCC cell migration and invasion; anti-IL-22 antibody reduced tumor number and tumor burden in a UV-induced SCC mouse model.\",\n      \"method\": \"T cell polarization assays, SCC cell invasion/migration assays, UV-induced SCC mouse model with anti-IL-22 antibody treatment\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vivo antibody blockade with in vitro mechanistic studies\",\n      \"pmids\": [\"27699266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17 and IL-22 together promote keratinocyte stemness in psoriasis by inducing upregulation of stemness markers (p63, CD44, CD29), increasing colony-forming efficiency and long-term proliferative capacity, and promoting an immature differentiation state; IL-22 induces these effects by acting directly on keratinocytes.\",\n      \"method\": \"Flow cytometry on lesional keratinocytes, cytokine treatment of normal keratinocytes, colony-forming efficiency assay\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — in vitro cytokine treatment with functional stemness readouts but no genetic pathway dissection\",\n      \"pmids\": [\"30684548\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-22 is a secreted cytokine that signals through a heterodimeric receptor complex (IL-22R1/CRF2-9 and IL-10R2), activating JAK1 and Tyk2, leading to STAT1, STAT3, and STAT5 tyrosine phosphorylation as well as ERK, JNK, and p38 MAPK pathways; STAT3 Ser727 phosphorylation is additionally required for maximal transcriptional activity; the primary mechanistic outputs of IL-22-STAT3 signaling in epithelial cells include induction of antimicrobial peptides, mucins, and acute phase reactants, promotion of epithelial proliferation and barrier integrity (via Tyk2), goblet cell hyperplasia, hepatocyte survival through antiapoptotic gene induction, and organ regeneration; IL-22 production is regulated upstream by AhR, STAT3 (via IL-21), NF-κB (via IL-18), HIF1α (via SCFAs/GPR41/HDAC inhibition), and PGE2/EP4/cAMP signaling, while its bioavailability is limited by soluble IL-22BP (IL-22Ra2) isoforms that act as a rheostat and are induced by TNF in dendritic cells; IL-22 further initiates an IL-22→STAT3→IL-18 epithelial response circuit that promotes intestinal stem cell expansion and barrier defense, and a negative feedback loop via STAT3-induced miR-197 that targets IL-22Ra1 to attenuate signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL-22 is a cytokine that acts on non-hematopoietic epithelial cells to drive tissue repair, barrier defense, and antimicrobial immunity through a heterodimeric receptor (IL-22RA1/IL-10R2) that activates STAT3, MAPK, and PI3K/AKT signaling. Receptor engagement triggers STAT3-dependent epithelial proliferation, goblet cell hyperplasia with mucin production, antimicrobial peptide expression (e.g., Reg3γ), and tight junction fortification, while also inducing hepatic complement C3 for systemic antibacterial defense [PMID:24130494, PMID:27456484, PMID:26432894, PMID:26497621]. IL-22 signaling is negatively regulated by a soluble decoy receptor IL-22BP (IL-22RA2), whose most potent isoform (IL-22BPi2) is induced by TLR2 and retinoic acid in myeloid cells, and by a STAT3-induced miR-197 feedback loop that targets IL-22RA1 mRNA [PMID:27678220, PMID:25208211]. In intestinal epithelium, IL-22 activates a pSTAT3→IL-18→Akt-Tcf4 relay that sustains stem cell expansion and crypt integrity, while chronic or high-level IL-22 inhibits WNT–β-catenin signaling and suppresses absorptive enterocyte differentiation [PMID:35169117, PMID:39317186, PMID:30364840].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Identifying IL-22BP as a soluble neutralizing receptor established that IL-22 bioavailability is actively regulated extracellularly, not just by receptor expression.\",\n      \"evidence\": \"Cloning of mouse IL-22BP, binding assays showing neutralization of IL-22-driven STAT3 phosphorylation and ROS in cell lines\",\n      \"pmids\": [\"12700595\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Isoform-specific functions of IL-22BP not yet resolved\", \"In vivo relevance of IL-22BP neutralization not demonstrated\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Characterizing IL-22R1 as the tissue-restricting receptor subunit explained why IL-22 acts selectively on epithelial and parenchymal tissues rather than immune cells.\",\n      \"evidence\": \"Receptor expression profiling across tissues, receptor complex characterization\",\n      \"pmids\": [\"15120651\", \"15201862\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type–specific receptor expression within tissues not resolved at single-cell level\", \"Signaling kinase identity downstream of receptor not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Genetic knockout studies established that IL-22 is dispensable for systemic intracellular pathogen control but required at mucosal surfaces, clarifying its niche as a barrier-defense cytokine rather than a general antimicrobial effector.\",\n      \"evidence\": \"IL-22−/− mice challenged with T. gondii (oral vs. i.p.) and M. avium; neutralization and KO in C. albicans infection\",\n      \"pmids\": [\"20220096\", \"20445503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream target genes mediating mucosal protection not individually validated\", \"Relative contribution of IL-22 vs. IL-17 at mucosal surfaces not fully disentangled\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that IL-22 directly drives goblet cell hyperplasia and mucin expression moved its function beyond antimicrobial peptide induction to encompass mucus barrier reinforcement.\",\n      \"evidence\": \"IL-22−/− mice with N. brasiliensis and T. muris infections; direct epithelial cell stimulation with recombinant IL-22\",\n      \"pmids\": [\"24130494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factor intermediaries linking STAT3 to mucin gene activation not identified\", \"Whether goblet cell effects are direct or require epithelial-stromal cross-talk unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Dissecting hepatoprotective versus hepatotoxic outcomes revealed that acute IL-22/STAT3 signaling protects hepatocytes, while chronic overexpression upregulates cytochrome P450 enzymes via HNF-1α to exacerbate toxicity — establishing dose and duration as critical determinants.\",\n      \"evidence\": \"Liver-specific STAT3 KO, IL-22 transgenic mice, Cyp2E1 KO, acetaminophen hepatotoxicity model\",\n      \"pmids\": [\"25063867\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"HNF-1α regulation by IL-22 not mechanistically dissected\", \"Threshold between protective and pathogenic IL-22 signaling not quantified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying IL-22 as a driver of kidney tubular regeneration via TLR4-triggered mononuclear cell secretion extended its tissue-repair function beyond gut and liver to kidney epithelium.\",\n      \"evidence\": \"IL-22 KO/blockade in AKI mice, cell depletion, rIL-22 rescue, TLR4 blockade\",\n      \"pmids\": [\"24459235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific STAT3 target genes in tubular cells not identified\", \"Whether IL-22 drives proliferation or anti-apoptosis in renal epithelium not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Uncovering the STAT3→miR-197→IL-22RA1 feedback loop revealed a cell-intrinsic mechanism that limits IL-22 responsiveness in keratinocytes, explaining how epithelial cells auto-attenuate cytokine signaling.\",\n      \"evidence\": \"ChIP for pSTAT3 at miR-197 promoter, 3′UTR reporter assay confirming IL22RA1 targeting, functional proliferation readout\",\n      \"pmids\": [\"25208211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relevance of miR-197 loop in intestinal epithelium not tested\", \"Whether other miRNAs co-regulate IL-22RA1 unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapping IL-22's activation of MAPK (JNK, ERK, p38) alongside STAT3 in keratinocytes, and showing that C/EBPα downregulation mediates differentiation inhibition, broadened the downstream signaling repertoire beyond STAT3 alone.\",\n      \"evidence\": \"Recombinant IL-22 stimulation of keratinocytes, western blot for MAPK phosphorylation, C/EBPα siRNA knockdown\",\n      \"pmids\": [\"32945375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of MAPK vs. STAT3 to proliferation not dissected with pathway-specific inhibitors in parallel\", \"Single cell type tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying Tyk2 as the kinase coupling IL-22RA1/IL-10R2 to STAT3 in intestinal epithelial cells resolved a key proximal signaling step and showed that IEC-intrinsic Tyk2 is required for colitis protection.\",\n      \"evidence\": \"Conditional IEC-specific Tyk2 KO, primary IEC pSTAT3 assay, colitis and C. rodentium models, rescue with rIL-22-Fc\",\n      \"pmids\": [\"26432894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Jak1 compensates partially for Tyk2 not excluded\", \"Tyk2-independent IL-22 target genes not characterized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Functional characterization of three human IL-22BP isoforms revealed that differential splicing, secretion competence, and inducibility (TLR2/retinoic acid) create a tiered antagonism system tuning IL-22 bioavailability in homeostasis versus inflammation.\",\n      \"evidence\": \"Isoform expression analysis, STAT3 signaling inhibition assays, TLR2/RA stimulation of myeloid cells\",\n      \"pmids\": [\"27678220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structures of isoform–IL-22 complexes not available\", \"In vivo isoform-specific deletion not performed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showing that hepatic IL-22RA1 drives C3 complement production for opsonization of S. pneumoniae established a liver–lung immune axis through which IL-22 confers systemic antibacterial defense beyond the local epithelial barrier.\",\n      \"evidence\": \"Hepatic-specific IL-22RA1 conditional KO, rIL-22 rescue, C3 binding assays, bacterial burden quantification\",\n      \"pmids\": [\"27456484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other acute-phase proteins are co-regulated not determined\", \"Mechanism of complement gene induction by STAT3 in hepatocytes not dissected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that IL-21/STAT3 controls the epigenetic state of the IL22 promoter in concert with AhR linked upstream cytokine signals and environmental sensors to IL-22 transcriptional regulation in T cells.\",\n      \"evidence\": \"STAT3 ChIP at IL22 promoter in CD4+ T cells, AhR inhibition/KO, ILC-deficient colitis model\",\n      \"pmids\": [\"24796415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific histone marks and chromatin remodelers involved not identified\", \"Whether same regulatory logic operates in ILC3s not shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying NF-κB p65 binding at the IL22 promoter downstream of IL-18 in ILC3s established a second transcriptional pathway for IL-22 induction, distinct from IL-21/STAT3/AhR in T cells.\",\n      \"evidence\": \"p65 ChIP on IL22 promoter, NF-κB activation assay, IL-18-driven ILC3 cytokine production, in situ co-localization in human tonsil\",\n      \"pmids\": [\"28842466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of NF-κB vs. AhR in ILC3s not compared\", \"Whether IL-18 and IL-21 pathways converge on the same promoter elements unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealing that high IL-22 concentrations suppress intestinal stem cell self-renewal and Wnt/Notch pathways while expanding transit-amplifying progenitors indicated that IL-22 dose determines whether it promotes regeneration or restricts stemness.\",\n      \"evidence\": \"Ileal organoid culture, scRNA-seq for IL22RA1 expression on ISC subsets, IL-22 transgenic mice\",\n      \"pmids\": [\"30364840\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which STAT3 suppresses Wnt in stem cells not resolved\", \"In vivo dose-response relationship not quantified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genetic epistasis in Il10−/−Il22−/− mice proved that IL-22 is required for colitis development in IL-10 deficiency, positioning IL-22 as a pathogenic driver when anti-inflammatory signals are absent and linking it to microbiome remodeling via antimicrobial gene induction.\",\n      \"evidence\": \"Double-KO mice, histology, Reg3g expression, microbiome sequencing\",\n      \"pmids\": [\"31932715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which IL-22 target genes are pathogenic vs. protective not individually dissected\", \"Source cells of IL-22 in Il10−/− colitis not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovering the IL-22→pSTAT3→IL-18→Akt-Tcf4 relay in intestinal crypts unified IL-22's epithelial signaling with stem cell expansion, demonstrating that IL-22 governs barrier defense partly through IL-18 as a downstream effector.\",\n      \"evidence\": \"STAT3 ChIP on Il-18 promoter, organoid budding assays, IL-22/IL-18 double-KO epistasis with AIEC infection\",\n      \"pmids\": [\"35169117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the IL-22→IL-18 relay operates in tissues beyond intestine not tested\", \"Akt-Tcf4 targets mediating stem cell expansion not catalogued\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing that TNF induces IL-22BP in colonic dendritic cells to suppress mucosal IL-22/STAT3 repair explained a mechanism by which inflammatory TNF paradoxically impairs epithelial healing, and provided a rationale for anti-TNF therapy restoring IL-22 bioavailability.\",\n      \"evidence\": \"Humanized colitis model, IL-22BP induction assay in DCs, pSTAT3 readout, IBD patient serum correlation\",\n      \"pmids\": [\"35383266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link in human IBD partly correlative\", \"Which IL-22BP isoform is TNF-induced not specified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cell-specific receptor KO demonstrated that IL-22 resolves metabolic steatotic liver disease through intestinal (not hepatic) IL-22RA1/STAT3 signaling that inhibits WNT–β-catenin to shrink the absorptive enterocyte compartment and reduce macronutrient absorption.\",\n      \"evidence\": \"IEC-specific vs. hepatocyte-specific IL-22RA1 KO, STAT3 and WNT pathway analysis, intestinal organoids, MASLD mouse model\",\n      \"pmids\": [\"39317186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific WNT pathway components targeted by STAT3 not identified\", \"Whether dietary composition modulates IL-22 efficacy not addressed\", \"Human translational data not yet available\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The dose-dependent switch between IL-22's regenerative and pathogenic or stem-cell-suppressive effects remains mechanistically unresolved, as does the integration of its multiple downstream relay circuits (STAT3→miR-197, STAT3→IL-18, STAT3→WNT inhibition) into a unified signaling model across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified quantitative model of dose-dependent signaling outcomes\", \"Tissue-specific transcriptional targets downstream of STAT3 not comprehensively mapped\", \"Structural basis of IL-22BP isoform differential inhibition unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 3, 4, 6, 8, 9, 12, 14, 20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 10, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 2, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 8, 12, 14, 15, 20, 25]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 9, 16, 17, 23]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IL22RA1\",\n      \"IL10RB\",\n      \"IL22RA2\",\n      \"STAT3\",\n      \"TYK2\",\n      \"AHR\",\n      \"IL18\",\n      \"IL21\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"IL-22 is a secreted cytokine of the IL-10 family that acts on epithelial cells and hepatocytes to promote antimicrobial defense, tissue repair, and barrier integrity across mucosal and hepatic surfaces. It signals through a heterodimeric receptor of IL-22R1 and IL-10R2, activating JAK1/Tyk2 and downstream STAT1/STAT3/STAT5, ERK/JNK/p38 MAPK, and PI3K/Akt pathways, with STAT3 Ser727 phosphorylation required for maximal transcriptional output [PMID:12087100, PMID:26432894, PMID:10875937]. STAT3-dependent targets include acute-phase reactants, antimicrobial peptides, mucins, complement C3, antiapoptotic proteins (Bcl-2, Bcl-xL, Mcl-1), and an IL-22→STAT3→IL-18 epithelial circuit that expands intestinal stem cells; IL-22 also drives goblet cell hyperplasia, keratinocyte proliferation, and enterocyte compartment remodeling via WNT–β-catenin inhibition [PMID:15122762, PMID:35169117, PMID:24130494, PMID:39317186]. IL-22 bioavailability is regulated by soluble IL-22BP isoforms—with IL-22BPi2 functioning as the principal antagonist—and its production is controlled by AhR, NF-κB (via IL-18), STAT3 (via IL-21), HIF1α (via SCFAs/GPR41), and PGE2/EP4/cAMP signaling, while a STAT3-induced miR-197 negative feedback loop targets IL-22R1 to attenuate signaling [PMID:27678220, PMID:21600206, PMID:28842466, PMID:32901017, PMID:28583370, PMID:25208211].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"The identity of IL-22 as a new IL-10 family cytokine and its two-chain receptor complex (IL-22R1/IL-10R2) were established, resolving the molecular basis for its signaling through STAT1, STAT3, and STAT5 and distinguishing it functionally from IL-10.\",\n      \"evidence\": \"Receptor binding, STAT activation assays, and anti-IL-10R2 blocking in hepatoma cell lines and COS cell reconstitution with domain-swap mutagenesis\",\n      \"pmids\": [\"10875937\", \"10657629\", \"10954742\", \"11035029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of the ternary IL-22/receptor complex was not resolved\", \"Tissue-level receptor distribution was incompletely mapped\", \"Relative contributions of each receptor chain to downstream signaling specificity were not fully defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The full intracellular signaling cascade downstream of IL-22 was mapped—JAK1/Tyk2 activation, STAT1/3/5 tyrosine phosphorylation, ERK/JNK/p38 MAPK, and the requirement for STAT3 Ser727 phosphorylation for maximal transcriptional activity—establishing the signaling framework underlying all subsequent functional studies.\",\n      \"evidence\": \"Phospho-specific immunoblots, kinase inhibitors, and STAT3 S727A mutant reporter assays in rat hepatoma cells\",\n      \"pmids\": [\"12087100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for STAT3 Ser727 phosphorylation downstream of IL-22 was not identified\", \"Contribution of individual MAPK branches to specific gene programs remained unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"IL-22 was shown to be a hepatocyte survival factor acting through STAT3 to induce antiapoptotic (Bcl-2, Bcl-xL, Mcl-1) and mitogenic (c-myc, cyclin D1) genes, establishing its cytoprotective role in the liver.\",\n      \"evidence\": \"In vivo IL-22 neutralization worsening T-cell hepatitis, stable IL-22 overexpression in HepG2 cells, STAT3 blockade abolishing effects\",\n      \"pmids\": [\"15122762\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STAT3-independent pathways contribute to hepatoprotection was not tested\", \"Duration and dose-dependence of protective versus potentially oncogenic STAT3 activation were unexplored\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Beyond hepatocytes, IL-22 was found to activate NF-κB and AP-1 in colonic subepithelial myofibroblasts, inducing proinflammatory cytokines and MMPs, revealing that IL-22 has pro-inflammatory outputs in mesenchymal cells in addition to its epithelial effects.\",\n      \"evidence\": \"EMSA for NF-κB/AP-1, MAPK inhibitors, ELISA in colonic myofibroblast cultures\",\n      \"pmids\": [\"16143135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of myofibroblast-directed signaling to intestinal pathology was not demonstrated\", \"Relative contribution of NF-κB versus AP-1 to specific gene targets was not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"IL-22 was shown to act directly on intestinal epithelial cells to drive proliferation, PI3K-dependent migration, and antimicrobial peptide (hBD-2) expression, establishing the intestinal epithelium as a primary target tissue.\",\n      \"evidence\": \"Signaling pathway analysis, PI3K inhibitor migration assay, and cytokine/defensin induction in IEC lines\",\n      \"pmids\": [\"16537974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo validation of PI3K-dependent migration in wound healing was lacking\", \"Receptor expression regulation in primary human IECs was not confirmed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The in vivo mucosal protective function of IL-22 was established in lung and gut: IL-22 protected lung epithelial barriers during Klebsiella pneumonia and was identified as the signature cytokine of mucosal NK-22 cells triggered by IL-23.\",\n      \"evidence\": \"IL-22 neutralization/KO in Klebsiella infection model; isolation and functional characterization of NK-22 cells from human tonsil and mouse lamina propria\",\n      \"pmids\": [\"18264110\", \"18978771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of NK-22 versus Th17/ILC3 sources to total mucosal IL-22 were not quantified\", \"Mechanism of IL-22-mediated transepithelial resistance increase was not molecularly defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"AhR was positioned upstream of IL-22 as a key transcriptional regulator: AhR agonism induced IL-22 and protected from experimental colitis, and IL-22 neutralization abolished the AhR-mediated protection, establishing the AhR→IL-22 axis. Separately, IL-22/STAT3 signaling was shown to promote hepatocellular carcinoma growth.\",\n      \"evidence\": \"AhR agonist/antagonist in multiple colitis models with IL-22 epistasis; IL-22 KO in diethylnitrosamine HCC model\",\n      \"pmids\": [\"21600206\", \"21674558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct AhR binding to the IL22 promoter was not demonstrated in this study\", \"Thresholds distinguishing protective versus tumorigenic IL-22/STAT3 activity were undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"IL-22 was found to directly induce goblet cell hyperplasia and mucin expression, and IL-22 KO mice showed impaired helminth expulsion, expanding the repertoire of IL-22 epithelial outputs beyond antimicrobial peptides to mucus barrier defense.\",\n      \"evidence\": \"IL-22 KO mice infected with Nippostrongylus brasiliensis and Trichuris muris, ex vivo and in vitro epithelial stimulation\",\n      \"pmids\": [\"24130494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factors mediating IL-22-driven goblet cell differentiation were not identified\", \"Whether IL-22 acts on goblet cell progenitors or mature goblet cells was not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Multiple regulatory and effector mechanisms converged: IL-21/STAT3 was shown to epigenetically control the IL22 locus in cooperation with AhR; IL-22→STAT3→DOT1L drove cancer stemness genes; IL-22→STAT3 directly induced IL-18 via promoter binding creating an epithelial defense circuit; and a STAT3→miR-197→IL-22R1 negative feedback loop was identified. Dual hepatoprotective/hepatotoxic roles were dissected by chronic versus acute IL-22 exposure affecting CYP2E1 via HNF-1α.\",\n      \"evidence\": \"ChIP for STAT3 at Il-18 and miR-197 promoters; organoid and KO epistasis (IL-22/IL-18); DOT1L expression with stemness gene assays; liver-specific STAT3 KO and CYP2E1 KO in IL-22 transgenic mice; IL-21-driven chromatin remodeling at il22 locus\",\n      \"pmids\": [\"24796415\", \"24816405\", \"35169117\", \"25208211\", \"25063867\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IL-22→IL-18 circuit operates in tissues beyond intestinal epithelium is unknown\", \"Quantitative dynamics of the miR-197 feedback loop in vivo were not established\", \"Threshold dose/duration distinguishing protective from oncogenic STAT3 signaling remains undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Tyk2 was established as the essential kinase transducing IL-22 signals in intestinal epithelial cells: IEC-specific Tyk2 KO reduced STAT3 phosphorylation and worsened colitis, which could be rescued by high-dose IL-22-Fc. Separately, hepatic IL-22 signaling was shown to induce C3 complement for bacterial opsonization during pneumonia.\",\n      \"evidence\": \"Conditional IEC-specific Tyk2 KO with Citrobacter rodentium colitis; hepatic-specific IL-22Ra1 KO with S. pneumoniae infection and C3 assays\",\n      \"pmids\": [\"26432894\", \"27456484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether JAK1 is equally required in IECs was not tested in conditional models\", \"Whether C3 induction is STAT3-dependent was not directly confirmed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"IL-22BP isoform biology was resolved: IL-22BPi2 is the principal secreted antagonist while IL-22BPi1 is retained intracellularly; TNF and TLR2/retinoic acid regulate isoform expression, establishing IL-22BP as a rheostat for IL-22/STAT3 signaling.\",\n      \"evidence\": \"Isoform-specific constructs, secretion assays, IL-22 STAT3 reporter assays, TLR2 and retinoic acid stimulation of myeloid cells\",\n      \"pmids\": [\"27678220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for differential IL-22 binding affinity of isoforms was not resolved\", \"In vivo isoform-specific functions in disease models were not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two upstream regulatory pathways were defined: NF-κB p65 directly binds the IL22 promoter downstream of IL-18 in ILC3s, and PGE2 induces IL-22 via EP4/cAMP in T cells, broadening the map of signals controlling IL-22 production.\",\n      \"evidence\": \"ChIP for p65 at IL22 promoter, ILC3 proliferation assays; T cell-specific EP4 KO with in vivo hapten sensitization\",\n      \"pmids\": [\"28842466\", \"28583370\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p65 and AhR cooperate at the IL22 promoter was not addressed\", \"cAMP effector (PKA vs EPAC) mediating EP4-driven IL-22 was not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Microbial metabolites (SCFAs) were linked to IL-22 production through GPR41, HDAC inhibition, and HIF1α direct binding to the Il22 promoter, connecting gut microbiota metabolism to mucosal IL-22 output. Separately, IL-22 was shown to be required for colitis in Il10−/− mice, shaping microbiome composition and epithelial hyperplasia.\",\n      \"evidence\": \"GPR41 KO, ChIP for HIF1α at Il22 promoter, histone modification assays; Il10−/−Il22−/− double KO genetic model with microbiome analysis\",\n      \"pmids\": [\"32901017\", \"31932715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific SCFAs (butyrate vs propionate) contributing most to HIF1α-driven IL-22 were not resolved\", \"How IL-22 shapes microbiome composition mechanistically is unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The TNF→IL-22BP axis in dendritic cells was identified as a mechanism restricting IL-22 bioavailability during colitis, explaining how anti-TNF therapy restores mucosal healing through increased IL-22/STAT3 signaling.\",\n      \"evidence\": \"Humanized colitis model, TNF source dissection (membrane-bound vs soluble), IL-22BP induction in DCs, correlation in IBD patient sera\",\n      \"pmids\": [\"35383266\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether anti-TNF effects on IL-22BP are sufficient to explain mucosal healing versus other anti-TNF mechanisms was not formally tested\", \"Isoform-specific regulation of IL-22BP by TNF was not fully characterized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"IL-22 was shown to resolve metabolic-associated steatotic liver disease (MASLD) by acting on intestinal—not hepatic—epithelial cells to activate STAT3 and suppress WNT–β-catenin signaling, shrinking the absorptive enterocyte compartment and reversing macronutrient absorption, establishing a gut-liver metabolic axis for IL-22.\",\n      \"evidence\": \"IEC-specific receptor studies, STAT3 and WNT–β-catenin signaling analysis, intestinal morphometry in diet-induced MASLD mouse model\",\n      \"pmids\": [\"39317186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether WNT–β-catenin suppression is a direct STAT3 transcriptional target or indirect was not fully resolved\", \"Translatability of the IEC-centric mechanism to human MASLD therapy is untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for differential IL-22BP isoform antagonism, the precise dose and temporal thresholds separating IL-22's protective versus tumorigenic STAT3 signaling, how IL-22 remodels the gut microbiome, and whether the IL-22→STAT3→IL-18 epithelial circuit operates across all barrier tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural model of IL-22/IL-22BPi2 versus IL-22BPi3 interaction not available\", \"No quantitative framework for protective versus oncogenic STAT3 thresholds\", \"Mechanism of microbiome remodeling by IL-22 remains undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 2, 3, 8, 10, 11, 23]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 21, 33]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 3, 5, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 8, 16, 25, 28, 30]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 11, 12, 13, 14, 20, 22, 31, 32, 35]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 4, 8, 10, 19, 34]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 24, 36]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [5, 21, 33]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IL22RA1\",\n      \"IL10RB\",\n      \"IL22RA2\",\n      \"STAT3\",\n      \"JAK1\",\n      \"TYK2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}