{"gene":"IL22","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2000,"finding":"The IL-TIF (IL-22) gene consists of 6 exons spanning ~6 kb and is located on human chromosome 12q15, 90 kb from the IFN-gamma gene and 27 kb from AK155. A DNA fragment from the IL-TIF promoter region is sufficient to confer IL-9-regulated expression in reporter assays, identifying a cis-regulatory element required for IL-9-induced IL-22 expression.","method":"Genomic sequencing, chromosomal mapping, luciferase reporter assay","journal":"Genes and immunity","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — reporter assay with defined promoter element in single study","pmids":["11197690"],"is_preprint":false},{"year":2005,"finding":"Crystal structure of IL-22 expressed in insect cells (Drosophila S2) determined at 2.6 Å resolution, revealing six molecules per asymmetric unit. N-linked glycosylation causes only minor structural changes to the cytokine, but 1–4 Å main-chain differences at regions corresponding to IL-22R1 and IL-10R2 binding sites were observed across monomers, providing structural insight into receptor recognition.","method":"X-ray crystallography (2.6 Å resolution), structural comparison","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional site mapping, single rigorous study","pmids":["15983417"],"is_preprint":false},{"year":2008,"finding":"IL-22 signals through STAT3 in epithelial tissues. IL-22 receptor expression is absent on immune cells but restricted to epithelial tissues, providing directionality of signaling from the immune system to tissues; STAT3 activation induces proliferative, anti-apoptotic, and anti-microbial pathways.","method":"Immunohistochemistry, gene array analysis, organotypic skin model","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — replicated across multiple studies with consistent STAT3 pathway placement","pmids":["19016525"],"is_preprint":false},{"year":2008,"finding":"IL-22 (but not IL-17) downregulates genes associated with keratinocyte terminal differentiation and causes epidermal alterations (acanthosis, hypogranularity) in an organotypic skin model, establishing a distinct downstream pathway from IL-17 in keratinocytes.","method":"Gene array analysis of cytokine-treated keratinocytes, organotypic skin model, immunohistochemistry","journal":"The British journal of dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene array plus organotypic model, single lab with two orthogonal methods","pmids":["18684158"],"is_preprint":false},{"year":2010,"finding":"IL-22 induces a systemic acute-phase response: using adenoviral-mediated delivery and systemic IL-22 protein administration, IL-22 was shown to modulate coagulation factors (fibrinogen, platelet numbers), blood cell counts, thymic atrophy, and body weight, and to induce hepatic production of fibrinogen, CXCL1, and serum amyloid A.","method":"Adenoviral delivery of IL-22, systemic IL-22 protein administration, biochemical and hematological analyses in mice","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two delivery methods (adenoviral + recombinant protein) in same study, defined hepatic mechanistic output","pmids":["20870942"],"is_preprint":false},{"year":2013,"finding":"IL-21 triggers IL-22 (but not IL-17) production in CD4+ T cells via STAT3; IL-21-activated STAT3 controls the epigenetic status of the il22 promoter and its interaction with the aryl hydrocarbon receptor (AhR). Both IL-21 and AhR signaling in T cells control IL-22 production and DSS-induced colitis in ILC-deficient mice.","method":"T cell differentiation assays, STAT3 activation assays, chromatin/epigenetic analysis of il22 promoter, AhR reporter assay, ILC-deficient mouse colitis model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (epigenetic, signaling, in vivo) in single study establishing IL-21→STAT3→AhR→IL-22 axis","pmids":["24796415"],"is_preprint":false},{"year":2013,"finding":"IL-22 directly induces goblet cell hyperplasia and expression of goblet cell markers including mucins in intestinal epithelium, establishing a mechanistic role for IL-22 in anti-helminth immunity via goblet cell activation.","method":"IL-22-deficient mouse infection models (Nippostrongylus brasiliensis, Trichuris muris), ex vivo and in vitro goblet cell marker induction assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse phenotype replicated in two independent helminth models plus in vitro confirmation","pmids":["24130494"],"is_preprint":false},{"year":2014,"finding":"IL-22 protects against APAP-induced hepatotoxicity via hepatic STAT3 activation; this protection is lost in liver-specific STAT3 knockout mice. Conversely, chronic IL-22 overexpression increases APAP susceptibility by upregulating Cyp2E1 through elevated HNF-1α, with Cyp2E1 ablation abolishing this enhanced toxicity.","method":"IL-22 transgenic mice, liver-specific STAT3 knockout mice, Cyp2E1 knockout mice, adenovirus-mediated IL-22 delivery, hepatotoxicity assays","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple genetic KO models with defined molecular pathway (STAT3, Cyp2E1, HNF-1α) in single rigorous study","pmids":["25063867"],"is_preprint":false},{"year":2014,"finding":"TLR4 signaling on intrarenal dendritic cells and macrophages, triggered by necrotic tubular cell-derived danger signals, induces IL-22 secretion, which then acts on tubular epithelial cells (expressing IL-22 receptor exclusively) to accelerate post-ischemic tubular regeneration. TLR4 blockade during the healing phase suppresses IL-22 and impairs kidney regeneration.","method":"IL-22 deficient mice, cell depletion experiments, IL-22 reconstitution, TLR4 blockade, in vitro necrotic cell/oxidative stress assays","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO, depletion, reconstitution, and in vitro mechanistic validation in single study","pmids":["24459235"],"is_preprint":false},{"year":2014,"finding":"IL-22 signals in the lung to control pneumococcal burden; hepatic IL-22R1 signaling is specifically required as mice with hepatic-specific deletion of Il22ra1 had higher bacterial burden. Systemic IL-22 administration increased hepatic C3 expression, improving opsonization of S. pneumoniae via C3 deposition.","method":"Il22-/- mice, hepatic-specific Il22ra1 knockout mice, rIL-22 administration, in vitro C3 expression assays, opsonic capacity assays","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO combined with reconstitution and defined molecular mechanism (hepatic C3 complement)","pmids":["27456484"],"is_preprint":false},{"year":2015,"finding":"IL-22 stimulates gastric cancer cell migration and invasion via IL-22R1/AKT/MMP-9 signaling: IL-22 increases AKT activation and MMP-9 production in a time- and dose-dependent manner; knockdown of IL-22R1 attenuates these effects, and AKT inhibition suppresses MMP-9 expression.","method":"IL-22 stimulation of SGC-7901 cells, siRNA knockdown of IL-22R1, AKT inhibitor, migration/invasion assays, Western blot","journal":"International journal of clinical and experimental pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor KD plus inhibitor epistasis in single lab, two orthogonal methods","pmids":["25120745"],"is_preprint":false},{"year":2015,"finding":"IL-22 promotes smooth muscle cell (SMC) dedifferentiation toward a synthetic phenotype: arterial SMCs express the IL-22 receptor, and in vitro IL-22 exposure downregulates alpha-actin and caldesmon gene expression. IL-22 deficiency in ApoE-/- mice reduced plaque size and maintained SMC contractile phenotype.","method":"IL-22-/-ApoE-/- double knockout mice, in vitro SMC treatment with IL-22, gene expression analysis, immunohistochemistry","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse plus in vitro receptor expression and functional assay in single study","pmids":["26298743"],"is_preprint":false},{"year":2015,"finding":"IL-22 signals in intestinal epithelial cells via Tyrosine kinase 2 (Tyk2), a JAK family member, to activate STAT3. Tyk2-deficient IECs show reduced p-STAT3 in response to IL-22 stimulation; IEC-specific Tyk2 knockout aggravates colitis; high-dose rIL-22-Fc rescues Tyk2 deficiency; Tyk2 also mediates IL-22 signaling during Citrobacter rodentium infection.","method":"Global and conditional (IEC-specific) Tyk2-/- mice, DSS colitis model, Citrobacter rodentium infection, primary IEC p-STAT3 stimulation assays, rIL-22-Fc rescue","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, rescue experiment, multiple disease models, and in vitro mechanistic validation","pmids":["26432894"],"is_preprint":false},{"year":2015,"finding":"IL-22 overexpression in colorectal cancer cells (via IL10R2 overexpression) promotes STAT3 phosphorylation along with increased AKT and ERK phosphorylation; IL-22, but not IL-10, phosphorylated STAT3 in HT29 cells overexpressing IL10R2.","method":"Transient overexpression of IL10R2 in HT29 cells, IL-22 stimulation, Western blot for p-STAT3/AKT/ERK, proliferation assays","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, cell-line overexpression, biochemical signaling endpoints","pmids":["26130064"],"is_preprint":false},{"year":2016,"finding":"Human IL-22 binding protein (IL-22BP) has three isoforms generated by alternative splicing with distinct activities: IL-22BPi2 is the most potent inhibitor and is upregulated by TLR2 signaling and retinoic acid in myeloid cells; IL-22BPi3 has less inhibitory activity but is more abundant under homeostatic conditions; IL-22BPi1 is not secreted and fails to antagonize IL-22 signaling. The isoforms collectively act as a rheostat for IL-22-dependent STAT3 responses.","method":"Isoform-specific inhibitory activity assays, secretion assays, myeloid cell activation with TLR2 ligands and retinoic acid, IL-22/IL-17 cooperative gene induction assays","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple isoforms functionally characterized with secretion, inhibition, and myeloid activation assays in single rigorous study","pmids":["27678220"],"is_preprint":false},{"year":2016,"finding":"IL-23 induces IL-22 production in neutrophils via RORγt and AhR transcription factors. IL-23-induced mTOR activation in neutrophils is required for expression of RORγt and AhR and subsequent IL-22 and IL-17 production; mTOR pathway blockade inhibits these effects.","method":"Neutrophil stimulation assays, mTOR inhibitor, RORγt and AhR expression analysis, neutrophil depletion in colitis model, IL-22 blockade","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway (IL-23→mTOR→RORγt/AhR→IL-22) with inhibitor epistasis, single lab","pmids":["27067005"],"is_preprint":false},{"year":2017,"finding":"NF-κB p65 binds to the proximal region of the IL22 promoter in ILC3s to promote transcriptional activity; IL-18 cooperates with IL-15 to induce ILC3 proliferation and drive IL-22 production via NF-κB. Dexamethasone suppresses IL-23-mediated IL-22 production in human and mouse ILC3s in part through NF-κB pathway modulation.","method":"ChIP assay (p65 binding to IL22 promoter), luciferase reporter assay, NF-κB inhibitor, IL-18/IL-15 stimulation of human ILC3s, dexamethasone treatment","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP and reporter assay directly demonstrate p65 binding to IL22 promoter, single lab with orthogonal methods","pmids":["28842466","29980608"],"is_preprint":false},{"year":2018,"finding":"IL-22 has a profibrotic function in hepatic stellate cells (HSCs) by enhancing TGF-β signaling in a p38 MAPK-dependent manner. IL-22RA1 knockout mice exhibit reduced fibrosis in response to thioacetamide and CCl4; blocking AhR or RORγt (upstream of IL-22) also reduces fibrosis.","method":"In vitro stimulation of primary HSCs with IL-22, p38 MAPK inhibitor, IL-22RA1 KO mice, two fibrosis models (TAA and CCl4), AhR/RORγt antagonists","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse, in vitro mechanistic (p38 MAPK), and two independent in vivo models in single study","pmids":["30366940"],"is_preprint":false},{"year":2018,"finding":"IL-22 promotes allergic airway inflammation by enabling synergy with TNF-α (but not IL-17A) to elicit neutrophil-dominated airway inflammation and airway hyperresponsiveness; intranasal IL-22 + TNF-α recapitulated neutrophil recruitment in wild-type mice, while IL-22 deficiency increased IFN-γ production and reduced eosinophil/neutrophil recruitment.","method":"IL-22-/- mice, epicutaneous sensitization OVA model, intranasal cytokine instillation, cytokine neutralization antibodies, TH22-polarized T cell adoptive transfer","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mice, adoptive transfer, and cytokine instillation experiments with defined IL-22/TNF-α mechanistic synergy","pmids":["29920352"],"is_preprint":false},{"year":2019,"finding":"IL-22 acts through Tyk2-STAT3 signaling in IECs; AhR in intestinal epithelial cells is required for optimal IL-22/STAT3 signaling — intestinal cell-specific AhR knockout reduces responsiveness to IL-22 in part by enhancing SOCS3 expression, which dampens STAT3 phosphorylation. Deletion of SOCS3 rescues pSTAT3 levels in AhR KO organoids.","method":"Intestinal cell-specific AhR KO mice and organoids, IL-22 stimulation, SOCS3 deletion, pSTAT3 measurement, AOM/DSS carcinogenesis model","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO, genetic rescue (SOCS3 deletion), and mechanistic epistasis in single rigorous study","pmids":["34755534"],"is_preprint":false},{"year":2019,"finding":"IL-22 suppresses HSV-2 replication in human cervical epithelial cells through the IL-22 receptor complex (IL-22R1 and IL-10R2), activating JAK/STAT signaling via phosphorylation of STAT1 and STAT3, inducing IFN-stimulated genes (ISG15, ISG56, OAS-1, OAS-2, Mx2) and increasing tight junction proteins (ZO-1 and Occludin).","method":"IL-22 treatment of End1/E6E7 cells, Western blot for p-STAT1/p-STAT3, ISG expression assays, tight junction protein analysis, HSV-2 infection assays","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor identification, signaling pathway (JAK/STAT), and downstream gene induction characterized in single study","pmids":["31344598"],"is_preprint":false},{"year":2019,"finding":"Runx1 and RORγt cooperatively upregulate IL-22 expression through a distal enhancer (CNS-32) located 32 kb upstream of the mouse Il22 promoter. Mutation of Runx1 and RORγt binding motifs in CNS-32 abrogated reporter activity; Runx1 overexpression promotes IL-22 via inducing RORγt and IL-23R; CBFB (Runx1 cofactor) knockdown limits IL-22 production.","method":"Reporter assay with CNS-32 enhancer element, binding motif mutagenesis, ChIP-seq for Runx1/RORγt occupancy and histone H4 acetylation, Runx1 overexpression, CBFB shRNA knockdown, Th22 differentiation assays","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP, reporter assay with mutagenesis, and gain/loss-of-function experiments in single rigorous study","pmids":["31028121"],"is_preprint":false},{"year":2020,"finding":"IL-23 and IL-2 activation of STAT5 is required for optimal IL-22 production in ILC3s. IL-23 induces a STAT3-STAT5 complex that binds IL-22 promoter DNA elements in ILC3s. Mice lacking STAT5a or STAT5b are more susceptible to C. rodentium-mediated colitis with reduced IL-22 production.","method":"STAT5a/STAT5b KO mice, colitis model, ChIP for STAT3-STAT5 complex binding to IL-22 promoter, human and mouse colonic LP ILC3 stimulation assays","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP of STAT3-STAT5 at IL-22 promoter plus KO mouse validation across mouse and human cells","pmids":["32332067"],"is_preprint":false},{"year":2020,"finding":"IL-6 and the aryl hydrocarbon receptor (AhR) transcription factor are required to polarize CD8+ T cells to an IL-22-producing Tc22 subset; Tc22 cells are highly cytolytic with a distinct cytokine profile and transcriptome relative to Tc1 cells.","method":"In vitro T cell polarization assays, AhR dependence assays, cytotoxicity assays, transcriptome analysis, tumor growth assays with polarized T cells","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro polarization with AhR requirement identified, single lab with multiple assays","pmids":["31964625"],"is_preprint":false},{"year":2021,"finding":"Vitamin D3 (1,25(OH)2D3) inhibits IL-22 production in Th22 cells through the vitamin D receptor (VDR) binding to a repressive vitamin D response element (VDRE) identified in the il22 promoter. T cells with a mutated VDR do not show this 1,25(OH)2D3-mediated inhibition.","method":"Th22 cell polarization from naïve human CD4+ T cells, VDR-mutated T cells, luciferase reporter assay with il22 promoter VDRE, 1,25(OH)2D3 treatment","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reporter assay with defined VDRE plus VDR-mutant functional validation in human T cells, single rigorous study","pmids":["34408754"],"is_preprint":false},{"year":2021,"finding":"Nrf2 regulates IL-22 production in CD4+ T cells via the AhR pathway: Nrf2 binds to ARE motifs in the Ahr promoter to induce its transcription, and CDDO-Im-mediated Nrf2 activation induces IL-22 in a manner abolished by CD4-specific Ahr knockout and by an AhR antagonist. Nrf2 also binds an ARE repressor in the Rorc gene, inhibiting RORγt-dependent IL-17A transactivation.","method":"Nrf2 activator (CDDO-Im), CD4-specific Ahr KO mice, ChIP for Nrf2 binding to Ahr and Rorc ARE motifs, luciferase reporter assay for Ahr promoter, AhR antagonist CH-223191","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP, reporter assay, KO mice, and pharmacological validation converge on Nrf2→AhR→IL-22 axis","pmids":["33648937"],"is_preprint":false},{"year":2021,"finding":"IL-22 unexpectedly signals on erythroid precursors, which express IL-22RA1. IL-22 blockade alleviates anemia in Riok2 haploinsufficient mice (a model of MDS del(5q)) and in wild-type mice; serum IL-22 is elevated in MDS del(5q) patients and in anemia of chronic kidney disease.","method":"Proteomic and transcriptomic analysis of erythroid precursors, IL-22RA1 expression on erythroid precursors, IL-22 blockade in Riok2f/+Vav1cre and WT mice, serum IL-22 quantification in patients","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — novel receptor expression identified, KO/blockade mouse models with in vivo functional validation, and human correlative data","pmids":["33753942"],"is_preprint":false},{"year":2022,"finding":"IL-22 promotes intestinal crypt immunity via induction of phospho-STAT3 binding to the IL-18 gene promoter in epithelial cells, establishing an IL-22→STAT3→IL-18 signaling axis. IL-18 in turn promotes Lgr5+ stem cell expansion via Akt-Tcf4 signaling and IFNγ+ T cell responses. Epistasis experiments show IL-22-STAT3 acts upstream of IL-18-mediated barrier defense: IL-22 cannot restore parameters in Il-18-/- mice, but IL-18 restores parameters in Il-22-/- mice.","method":"Intestinal organoid culture, AIEC infection model, IL-22-/- and IL-18-/- mice, p-STAT3 ChIP on Il-18 promoter, cytokine rescue experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP, genetic epistasis with double KO, organoid assays, and in vivo infection model in single rigorous study","pmids":["35169117"],"is_preprint":false},{"year":2022,"finding":"IL-22 signals in glioblastoma (GBM) cells via IL-22R1/IL-10R2 receptor complex to activate STAT3 and PI3K/AKT pathways, increasing Bcl-xL (anti-apoptotic) and decreasing p-ERK1/2, resulting in cell survival and proliferation. All 10 primary GBM cell lines tested expressed IL-22R subunits.","method":"RT-PCR, Western blot, confocal microscopy for IL-22R expression, BrdU proliferation assay, ELISA cell death assay, phospho-protein analysis in GBM lines","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor characterization plus downstream signaling validated across multiple cell lines, single lab","pmids":["25793261"],"is_preprint":false},{"year":2022,"finding":"TNF induces IL-22BP (IL-22Ra2) expression in colonic dendritic cells via soluble TNF produced by IECs, thereby restricting IL-22/STAT3-mediated mucosal repair; anti-TNF therapy increases IL-22 bioavailability and IL-22-driven epithelial healing. Membrane-bound TNF from T cells perpetuates inflammation, while soluble TNF from IECs specifically drives IL-22BP induction in DCs.","method":"Humanized colitis model, TNF blockade experiments, IL-22BP induction in DCs, IL-22/STAT3-mediated repair assays, human monocyte-derived DC experiments, patient serum correlations","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — humanized model, DC cell experiments, mechanistic TNF→IL-22BP axis, and human clinical correlation in single study","pmids":["35383266"],"is_preprint":false},{"year":2023,"finding":"IL-22 signals on proximal tubule cells (PTCs) via IL-22RA1 to amplify the DNA damage response (DDR), promoting cell death in AKI. PTCs are identified as a source of urinary IL-22; global IL-22 deletion and tubule-specific IL-22RA1 knockout both protect against cisplatin- or aristolochic acid-induced AKI by reducing DDR component expression and PTC cell death.","method":"Cisplatin and aristolochic acid AKI models, IL-22 global KO mice, tubule-specific IL-22RA1 KO (IL-22RA1ΔTub), primary PTC IL-22 stimulation, urinary IL-22 measurement","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 / Strong — global and tissue-specific KO with two injury models, in vitro PTC signaling, novel PTC source and receptor identification","pmids":["38054920"],"is_preprint":false},{"year":2024,"finding":"IL-22 resolves MASLD by signaling through its IEC receptor (not hepatocytes) to activate STAT3 and inhibit WNT-β-catenin signaling, thereby shrinking the absorptive enterocyte compartment and reducing macronutrient absorption. Exogenous IL-22 reverses hepatosteatosis, inflammation, fibrosis, and insulin resistance.","method":"Recombinant IL-22 administration in diet-induced MASLD mice, IEC-specific vs. hepatocyte-specific signaling analysis, STAT3 activation, WNT-β-catenin pathway assays","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific receptor targeting established, multiple disease endpoints reversed, defined STAT3/WNT-β-catenin mechanism","pmids":["39317186"],"is_preprint":false},{"year":2024,"finding":"IL-22Ra1 signaling in MATH1+ intestinal cells (goblet and progenitor cells) is essential for maintaining mucosal barrier function and tissue regeneration. IL-22Ra1 signaling promotes mucin core-2 O-glycan extension by inducing B3GALT5 expression; adenoviral B3galt5 expression rescues Il22Ra1IEC mice from DSS colitis. B3GALT5 and Tn antigen expression are reduced in ulcerative colitis patient colon tissue.","method":"MATH1+ cell-specific Il22Ra1 conditional KO mice, DSS colitis model, adenoviral B3galt5 rescue, glycan analysis, organoid assays, human UC tissue analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO, adenoviral rescue, glycan mechanism defined, and human tissue validation in single rigorous study","pmids":["38733584"],"is_preprint":false}],"current_model":"IL-22 is a cytokine that signals exclusively through the heterodimeric IL-22R1/IL-10R2 receptor complex on non-hematopoietic epithelial cells (skin, gut, liver, lung, kidney), activating JAK1/Tyk2-STAT3 as its primary downstream pathway, with additional activation of AKT, ERK, and p38 MAPK; its transcription is controlled by a regulatory circuit involving AhR, RORγt, Runx1, STAT3, STAT5, NF-κB p65, and is repressed by vitamin D receptor binding a repressive VDRE in the il22 promoter; IL-22 drives epithelial proliferation, anti-apoptosis (via Bcl-xL), antimicrobial peptide production, goblet cell hyperplasia and mucin O-glycosylation, intestinal barrier repair (through an IL-22→STAT3→IL-18→Akt-Tcf4 axis), acute-phase responses in liver (via C3, fibrinogen, SAA induction), and tissue-specific pathological effects including HSC-mediated liver fibrosis (via TGF-β/p38 MAPK), SMC dedifferentiation in atherosclerosis, and erythroid suppression via unexpected IL-22RA1 expression on erythroid precursors; its bioavailability is antagonized by the soluble decoy receptor IL-22BP (IL-22RA2), which exists in three human isoforms with distinct inhibitory potencies regulated by TLR2 and retinoic acid signaling in myeloid cells."},"narrative":{"mechanistic_narrative":"IL-22 is a cytokine that mediates directional communication from the immune system to epithelial tissues, signaling through an IL-22R1/IL-10R2 receptor complex whose expression is restricted to non-hematopoietic epithelial cells while being absent on immune cells [PMID:19016525, PMID:31344598]. Receptor engagement activates a JAK family kinase Tyk2 to drive STAT3 phosphorylation, with intestinal epithelial AhR sustaining this response by limiting SOCS3-mediated STAT3 dampening [PMID:26432894, PMID:34755534]; additional STAT1, AKT, and ERK arms are engaged in a tissue- and context-dependent manner [PMID:26130064, PMID:31344598, PMID:25793261]. Downstream of STAT3, IL-22 promotes epithelial proliferation, anti-apoptosis, and antimicrobial defense, and in the intestine it enforces barrier integrity through a STAT3-driven IL-18 axis that expands Lgr5+ stem cells via Akt-Tcf4 and through induction of B3GALT5-dependent mucin core-2 O-glycosylation and goblet cell hyperplasia [PMID:35169117, PMID:38733584, PMID:24130494]. Systemically, hepatic IL-22-STAT3 signaling drives acute-phase and complement (C3) responses that promote antimicrobial opsonization and tissue protection [PMID:20870942, PMID:27456484, PMID:25063867]. IL-22 transcription is governed by a multifactorial circuit in which RORγt and Runx1/CBFB act through a distal CNS-32 enhancer, AhR, STAT3, STAT5, and NF-κB p65 promote expression in T cells and innate lymphoid cells, and signals including IL-21, IL-23, IL-2, IL-6, Nrf2, and retinoic acid feed into this network, while vitamin D receptor binding a repressive VDRE shuts it down [PMID:31028121, PMID:24796415, PMID:28842466, PMID:29980608, PMID:32332067, PMID:33648937, PMID:34408754]. IL-22 bioavailability is set by the soluble decoy IL-22BP (IL-22RA2), whose three splice isoforms differ in potency and whose induction is controlled by TLR2, retinoic acid, and TNF signaling in myeloid and dendritic cells [PMID:27678220, PMID:35383266]. Beyond protective roles, IL-22 has context-dependent pathological effects, including p38 MAPK-dependent enhancement of TGF-β signaling in hepatic stellate cell fibrosis, smooth muscle cell dedifferentiation in atherosclerosis, amplification of the DNA damage response in proximal tubule injury, suppression of erythropoiesis via IL-22RA1 on erythroid precursors, and promotion of tumor cell survival and invasion [PMID:30366940, PMID:26298743, PMID:38054920, PMID:33753942, PMID:25793261].","teleology":[{"year":2000,"claim":"Establishing the genomic structure and a cis-regulatory element answered where IL-22 sits in the genome and how its expression is first controlled, linking it to IL-9-induced transcription.","evidence":"Genomic sequencing, chromosomal mapping, and luciferase reporter assay of the IL-TIF promoter","pmids":["11197690"],"confidence":"Medium","gaps":["Did not identify the transcription factors binding the IL-9-responsive element","No protein-level functional characterization"]},{"year":2005,"claim":"The crystal structure defined the cytokine fold and mapped surfaces corresponding to IL-22R1 and IL-10R2 contacts, providing the structural basis for receptor recognition.","evidence":"X-ray crystallography at 2.6 Å of insect-cell-expressed IL-22 with structural comparison across monomers","pmids":["15983417"],"confidence":"High","gaps":["No co-crystal structure with the receptor heterodimer","Functional consequence of the main-chain differences at binding sites not tested"]},{"year":2008,"claim":"Restriction of IL-22 receptor expression to epithelial tissues and the central role of STAT3 established the directionality of IL-22 signaling from immune cells to tissue and distinguished its effects from IL-17.","evidence":"Immunohistochemistry, gene array, and organotypic skin model with keratinocyte differentiation readouts","pmids":["19016525","18684158"],"confidence":"Medium","gaps":["JAK kinase mediating STAT3 activation not yet defined","Mechanism of receptor exclusion from immune cells unknown"]},{"year":2010,"claim":"Systemic IL-22 delivery revealed a hepatic acute-phase program, showing IL-22 acts beyond local epithelia to modulate coagulation factors and serum proteins.","evidence":"Adenoviral and recombinant IL-22 administration in mice with hematological and biochemical analyses","pmids":["20870942"],"confidence":"Medium","gaps":["Did not establish hepatic STAT3 dependence directly","Physiological versus pharmacological relevance of systemic doses unclear"]},{"year":2013,"claim":"Defining the IL-21→STAT3→AhR and RORγt pathways and goblet cell induction answered how IL-22 is transcriptionally induced in T cells and how it executes mucosal anti-helminth defense.","evidence":"T cell differentiation, il22 promoter epigenetic/AhR analysis, ILC-deficient colitis model, and IL-22-KO helminth infection models","pmids":["24796415","24130494"],"confidence":"High","gaps":["Relative contribution of T cells versus ILCs to IL-22 in vivo not fully resolved","Goblet cell transcriptional targets downstream of IL-22 not detailed"]},{"year":2014,"claim":"Tissue-specific genetic studies in liver, kidney, and lung dissected dual protective and detrimental hepatic STAT3 outcomes and a hepatic C3-complement mechanism, defining IL-22 as an organ-protective and regenerative cytokine.","evidence":"Liver-specific STAT3 KO, Cyp2E1 KO, hepatic-specific Il22ra1 KO, IL-22-KO kidney injury models, and reconstitution/blockade experiments","pmids":["25063867","24459235","27456484"],"confidence":"High","gaps":["Determinants switching IL-22 between protective and toxic outcomes not defined","Cell-of-origin of IL-22 in each tissue not fully resolved"]},{"year":2015,"claim":"Identification of Tyk2 as the JAK mediating epithelial STAT3 activation, plus pathological signaling in cancer and smooth muscle, established the proximal signaling kinase and the context-dependent breadth of IL-22 effects.","evidence":"IEC-specific Tyk2 KO with rescue and infection/colitis models, IL-22R1 knockdown in gastric cancer cells, and IL-22-/-ApoE-/- atherosclerosis model","pmids":["26432894","25120745","26298743","26130064"],"confidence":"High","gaps":["Whether Tyk2 is the dominant JAK in non-intestinal tissues not tested","AKT/ERK arm activation mechanisms in tumor cells incompletely defined"]},{"year":2016,"claim":"Functional characterization of the three IL-22BP isoforms and their myeloid regulation defined the decoy rheostat controlling IL-22 bioavailability, and identification of RORγt/AhR-dependent neutrophil production added a cellular source.","evidence":"Isoform-specific inhibition and secretion assays with TLR2/retinoic acid myeloid activation, and neutrophil mTOR-RORγt/AhR pathway with inhibitor epistasis","pmids":["27678220","27067005"],"confidence":"High","gaps":["In vivo contribution of each IL-22BP isoform not separately measured","Structural basis of differential isoform potency unknown"]},{"year":2017,"claim":"ChIP and reporter evidence that NF-κB p65 binds the IL22 promoter in ILC3s, with IL-18/IL-15 cooperation, expanded the transcriptional circuit controlling IL-22 in innate lymphoid cells.","evidence":"ChIP and luciferase reporter assays, NF-κB inhibition, and cytokine stimulation of human ILC3s","pmids":["28842466","29980608"],"confidence":"High","gaps":["Integration of NF-κB with STAT and AhR inputs on the promoter not mapped","Dexamethasone target genes beyond NF-κB modulation not defined"]},{"year":2018,"claim":"Defining a p38 MAPK-dependent profibrotic role in hepatic stellate cells and TNF-α synergy in airway inflammation established that IL-22 can be pathogenic through tissue-specific and cytokine-context effects.","evidence":"IL-22RA1 KO with two fibrosis models and HSC p38 inhibition, plus IL-22-/- mice with intranasal cytokine and adoptive transfer airway models","pmids":["30366940","29920352"],"confidence":"High","gaps":["How epithelial STAT3 versus HSC p38 outputs are partitioned not resolved","Mechanism of IL-22/TNF-α synergy at the receptor/signaling level not defined"]},{"year":2019,"claim":"Epithelial AhR was shown to sustain IL-22/STAT3 signaling by restraining SOCS3, and the IL-22R complex was shown to drive antiviral ISG induction and barrier proteins, refining how responsiveness to IL-22 is calibrated and expanding its antiviral role.","evidence":"Intestinal AhR KO organoids with SOCS3 deletion rescue and pSTAT3 readouts, and IL-22 stimulation of cervical epithelial cells with ISG/tight junction assays","pmids":["34755534","31344598"],"confidence":"High","gaps":["Mechanism by which AhR represses SOCS3 not defined","STAT1 versus STAT3 contributions to antiviral ISGs not separated"]},{"year":2019,"claim":"Identification of the CNS-32 enhancer bound cooperatively by Runx1/CBFB and RORγt defined a distal cis-regulatory module driving IL-22 transcription.","evidence":"Reporter assay with motif mutagenesis, ChIP-seq for Runx1/RORγt occupancy, and Runx1 gain-of-function with CBFB knockdown","pmids":["31028121"],"confidence":"High","gaps":["Interplay between CNS-32 and proximal promoter elements not integrated","Human conservation of CNS-32 function not tested"]},{"year":2020,"claim":"STAT5 (downstream of IL-23/IL-2) forming a STAT3-STAT5 complex on the IL-22 promoter, and AhR-dependent Tc22 CD8 polarization, further resolved the signaling inputs and cellular sources generating IL-22.","evidence":"STAT5a/STAT5b KO colitis models with ChIP of the STAT3-STAT5 complex, and in vitro AhR-dependent CD8 polarization with cytotoxicity and tumor assays","pmids":["32332067","31964625"],"confidence":"High","gaps":["Stoichiometry and assembly of the STAT3-STAT5 complex unknown","In vivo significance of Tc22 cells not established"]},{"year":2021,"claim":"Vitamin D/VDR repression via a promoter VDRE, Nrf2-driven induction of AhR, and an unexpected IL-22RA1-dependent effect on erythroid precursors expanded both the repressive transcriptional control and the target cell repertoire of IL-22.","evidence":"VDR-mutant Th22 cells with VDRE reporter, Nrf2 activator/CD4 AhR KO with ARE ChIP, and erythroid precursor profiling with IL-22 blockade in mouse anemia models and patient serum","pmids":["34408754","33648937","33753942"],"confidence":"High","gaps":["Whether VDR and Nrf2 inputs operate in the same cells not addressed","Downstream signaling of IL-22 in erythroid precursors not detailed"]},{"year":2022,"claim":"An IL-22→STAT3→IL-18→Akt-Tcf4 axis and a TNF→IL-22BP decoy circuit defined how IL-22 directs stem cell-driven barrier defense and how its activity is suppressed during inflammation, with direct therapeutic relevance to anti-TNF response.","evidence":"Organoid/AIEC infection with IL-22-/-/IL-18-/- epistasis and p-STAT3 ChIP on Il-18, plus humanized colitis with DC IL-22BP induction and patient correlation; GBM receptor signaling characterized in parallel","pmids":["35169117","35383266","25793261"],"confidence":"High","gaps":["How soluble versus membrane TNF differentially engage DCs mechanistically not fully resolved","Generality of the IL-18 axis outside the intestine untested"]},{"year":2023,"claim":"Demonstration that IL-22 amplifies the DNA damage response in proximal tubule cells to promote cell death in AKI clarified a damaging, injury-context role distinct from its regenerative effects.","evidence":"Cisplatin/aristolochic acid AKI in global IL-22 KO and tubule-specific IL-22RA1 KO mice with primary PTC stimulation and urinary IL-22 measurement","pmids":["38054920"],"confidence":"High","gaps":["Molecular link between IL-22R signaling and DDR component induction not defined","Reconciliation with earlier protective kidney regeneration role not established"]},{"year":2024,"claim":"Showing IL-22 resolves MASLD through IEC (not hepatocyte) STAT3 signaling that inhibits WNT-β-catenin to shrink the absorptive compartment, and through MATH1+ cell B3GALT5-dependent mucin glycosylation, refined the target cell and effector mechanisms of metabolic and barrier protection.","evidence":"Recombinant IL-22 in diet-induced MASLD with IEC versus hepatocyte signaling analysis, and MATH1+ cell-specific Il22Ra1 KO with adenoviral B3galt5 rescue, glycan analysis, and human UC tissue","pmids":["39317186","38733584"],"confidence":"High","gaps":["How IL-22-STAT3 inhibits WNT-β-catenin mechanistically not defined","Whether enterocyte-shrinking mechanism applies in human metabolic disease untested"]},{"year":null,"claim":"What determines the switch between IL-22's protective/regenerative and pathological/pro-death outputs in the same epithelial tissue remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unifying model for context-dependent IL-22 outcomes","Receptor-proximal signaling differences between protective and damaging contexts undefined","Therapeutic window for IL-22 agonism versus blockade unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[2,20,28]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,12,20]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[4,14,30]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,12,20]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,9,14]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,16,21,22,24,25]}],"complexes":[],"partners":["IL22RA1","IL10R2","IL22RA2"],"other_free_text":[]}},"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":"18684158","id":"PMC_18684158","title":"Th17 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\"The IL-TIF (IL-22) gene consists of 6 exons spanning ~6 kb and is located on human chromosome 12q15, 90 kb from the IFN-gamma gene and 27 kb from AK155. A DNA fragment from the IL-TIF promoter region is sufficient to confer IL-9-regulated expression in reporter assays, identifying a cis-regulatory element required for IL-9-induced IL-22 expression.\",\n      \"method\": \"Genomic sequencing, chromosomal mapping, luciferase reporter assay\",\n      \"journal\": \"Genes and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — reporter assay with defined promoter element in single study\",\n      \"pmids\": [\"11197690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of IL-22 expressed in insect cells (Drosophila S2) determined at 2.6 Å resolution, revealing six molecules per asymmetric unit. N-linked glycosylation causes only minor structural changes to the cytokine, but 1–4 Å main-chain differences at regions corresponding to IL-22R1 and IL-10R2 binding sites were observed across monomers, providing structural insight into receptor recognition.\",\n      \"method\": \"X-ray crystallography (2.6 Å resolution), structural comparison\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional site mapping, single rigorous study\",\n      \"pmids\": [\"15983417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-22 signals through STAT3 in epithelial tissues. IL-22 receptor expression is absent on immune cells but restricted to epithelial tissues, providing directionality of signaling from the immune system to tissues; STAT3 activation induces proliferative, anti-apoptotic, and anti-microbial pathways.\",\n      \"method\": \"Immunohistochemistry, gene array analysis, organotypic skin model\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — replicated across multiple studies with consistent STAT3 pathway placement\",\n      \"pmids\": [\"19016525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-22 (but not IL-17) downregulates genes associated with keratinocyte terminal differentiation and causes epidermal alterations (acanthosis, hypogranularity) in an organotypic skin model, establishing a distinct downstream pathway from IL-17 in keratinocytes.\",\n      \"method\": \"Gene array analysis of cytokine-treated keratinocytes, organotypic skin model, immunohistochemistry\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene array plus organotypic model, single lab with two orthogonal methods\",\n      \"pmids\": [\"18684158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-22 induces a systemic acute-phase response: using adenoviral-mediated delivery and systemic IL-22 protein administration, IL-22 was shown to modulate coagulation factors (fibrinogen, platelet numbers), blood cell counts, thymic atrophy, and body weight, and to induce hepatic production of fibrinogen, CXCL1, and serum amyloid A.\",\n      \"method\": \"Adenoviral delivery of IL-22, systemic IL-22 protein administration, biochemical and hematological analyses in mice\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two delivery methods (adenoviral + recombinant protein) in same study, defined hepatic mechanistic output\",\n      \"pmids\": [\"20870942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL-21 triggers IL-22 (but not IL-17) production in CD4+ T cells via STAT3; IL-21-activated STAT3 controls the epigenetic status of the il22 promoter and its interaction with the aryl hydrocarbon receptor (AhR). Both IL-21 and AhR signaling in T cells control IL-22 production and DSS-induced colitis in ILC-deficient mice.\",\n      \"method\": \"T cell differentiation assays, STAT3 activation assays, chromatin/epigenetic analysis of il22 promoter, AhR reporter assay, ILC-deficient mouse colitis model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (epigenetic, signaling, in vivo) in single study establishing IL-21→STAT3→AhR→IL-22 axis\",\n      \"pmids\": [\"24796415\"],\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 epithelium, establishing a mechanistic role for IL-22 in anti-helminth immunity via goblet cell activation.\",\n      \"method\": \"IL-22-deficient mouse infection models (Nippostrongylus brasiliensis, Trichuris muris), ex vivo and in vitro goblet cell marker induction assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse phenotype replicated in two independent helminth models plus in vitro confirmation\",\n      \"pmids\": [\"24130494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-22 protects against APAP-induced hepatotoxicity via hepatic STAT3 activation; this protection is lost in liver-specific STAT3 knockout mice. Conversely, chronic IL-22 overexpression increases APAP susceptibility by upregulating Cyp2E1 through elevated HNF-1α, with Cyp2E1 ablation abolishing this enhanced toxicity.\",\n      \"method\": \"IL-22 transgenic mice, liver-specific STAT3 knockout mice, Cyp2E1 knockout mice, adenovirus-mediated IL-22 delivery, hepatotoxicity assays\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple genetic KO models with defined molecular pathway (STAT3, Cyp2E1, HNF-1α) in single rigorous study\",\n      \"pmids\": [\"25063867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TLR4 signaling on intrarenal dendritic cells and macrophages, triggered by necrotic tubular cell-derived danger signals, induces IL-22 secretion, which then acts on tubular epithelial cells (expressing IL-22 receptor exclusively) to accelerate post-ischemic tubular regeneration. TLR4 blockade during the healing phase suppresses IL-22 and impairs kidney regeneration.\",\n      \"method\": \"IL-22 deficient mice, cell depletion experiments, IL-22 reconstitution, TLR4 blockade, in vitro necrotic cell/oxidative stress assays\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO, depletion, reconstitution, and in vitro mechanistic validation in single study\",\n      \"pmids\": [\"24459235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-22 signals in the lung to control pneumococcal burden; hepatic IL-22R1 signaling is specifically required as mice with hepatic-specific deletion of Il22ra1 had higher bacterial burden. Systemic IL-22 administration increased hepatic C3 expression, improving opsonization of S. pneumoniae via C3 deposition.\",\n      \"method\": \"Il22-/- mice, hepatic-specific Il22ra1 knockout mice, rIL-22 administration, in vitro C3 expression assays, opsonic capacity assays\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO combined with reconstitution and defined molecular mechanism (hepatic C3 complement)\",\n      \"pmids\": [\"27456484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-22 stimulates gastric cancer cell migration and invasion via IL-22R1/AKT/MMP-9 signaling: IL-22 increases AKT activation and MMP-9 production in a time- and dose-dependent manner; knockdown of IL-22R1 attenuates these effects, and AKT inhibition suppresses MMP-9 expression.\",\n      \"method\": \"IL-22 stimulation of SGC-7901 cells, siRNA knockdown of IL-22R1, AKT inhibitor, migration/invasion assays, Western blot\",\n      \"journal\": \"International journal of clinical and experimental pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor KD plus inhibitor epistasis in single lab, two orthogonal methods\",\n      \"pmids\": [\"25120745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-22 promotes smooth muscle cell (SMC) dedifferentiation toward a synthetic phenotype: arterial SMCs express the IL-22 receptor, and in vitro IL-22 exposure downregulates alpha-actin and caldesmon gene expression. IL-22 deficiency in ApoE-/- mice reduced plaque size and maintained SMC contractile phenotype.\",\n      \"method\": \"IL-22-/-ApoE-/- double knockout mice, in vitro SMC treatment with IL-22, gene expression analysis, immunohistochemistry\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse plus in vitro receptor expression and functional assay in single study\",\n      \"pmids\": [\"26298743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-22 signals in intestinal epithelial cells via Tyrosine kinase 2 (Tyk2), a JAK family member, to activate STAT3. Tyk2-deficient IECs show reduced p-STAT3 in response to IL-22 stimulation; IEC-specific Tyk2 knockout aggravates colitis; high-dose rIL-22-Fc rescues Tyk2 deficiency; Tyk2 also mediates IL-22 signaling during Citrobacter rodentium infection.\",\n      \"method\": \"Global and conditional (IEC-specific) Tyk2-/- mice, DSS colitis model, Citrobacter rodentium infection, primary IEC p-STAT3 stimulation assays, rIL-22-Fc rescue\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, rescue experiment, multiple disease models, and in vitro mechanistic validation\",\n      \"pmids\": [\"26432894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-22 overexpression in colorectal cancer cells (via IL10R2 overexpression) promotes STAT3 phosphorylation along with increased AKT and ERK phosphorylation; IL-22, but not IL-10, phosphorylated STAT3 in HT29 cells overexpressing IL10R2.\",\n      \"method\": \"Transient overexpression of IL10R2 in HT29 cells, IL-22 stimulation, Western blot for p-STAT3/AKT/ERK, proliferation assays\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, cell-line overexpression, biochemical signaling endpoints\",\n      \"pmids\": [\"26130064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Human IL-22 binding protein (IL-22BP) has three isoforms generated by alternative splicing with distinct activities: IL-22BPi2 is the most potent inhibitor and is upregulated by TLR2 signaling and retinoic acid in myeloid cells; IL-22BPi3 has less inhibitory activity but is more abundant under homeostatic conditions; IL-22BPi1 is not secreted and fails to antagonize IL-22 signaling. The isoforms collectively act as a rheostat for IL-22-dependent STAT3 responses.\",\n      \"method\": \"Isoform-specific inhibitory activity assays, secretion assays, myeloid cell activation with TLR2 ligands and retinoic acid, IL-22/IL-17 cooperative gene induction assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple isoforms functionally characterized with secretion, inhibition, and myeloid activation assays in single rigorous study\",\n      \"pmids\": [\"27678220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-23 induces IL-22 production in neutrophils via RORγt and AhR transcription factors. IL-23-induced mTOR activation in neutrophils is required for expression of RORγt and AhR and subsequent IL-22 and IL-17 production; mTOR pathway blockade inhibits these effects.\",\n      \"method\": \"Neutrophil stimulation assays, mTOR inhibitor, RORγt and AhR expression analysis, neutrophil depletion in colitis model, IL-22 blockade\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway (IL-23→mTOR→RORγt/AhR→IL-22) with inhibitor epistasis, single lab\",\n      \"pmids\": [\"27067005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NF-κB p65 binds to the proximal region of the IL22 promoter in ILC3s to promote transcriptional activity; IL-18 cooperates with IL-15 to induce ILC3 proliferation and drive IL-22 production via NF-κB. Dexamethasone suppresses IL-23-mediated IL-22 production in human and mouse ILC3s in part through NF-κB pathway modulation.\",\n      \"method\": \"ChIP assay (p65 binding to IL22 promoter), luciferase reporter assay, NF-κB inhibitor, IL-18/IL-15 stimulation of human ILC3s, dexamethasone treatment\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP and reporter assay directly demonstrate p65 binding to IL22 promoter, single lab with orthogonal methods\",\n      \"pmids\": [\"28842466\", \"29980608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-22 has a profibrotic function in hepatic stellate cells (HSCs) by enhancing TGF-β signaling in a p38 MAPK-dependent manner. IL-22RA1 knockout mice exhibit reduced fibrosis in response to thioacetamide and CCl4; blocking AhR or RORγt (upstream of IL-22) also reduces fibrosis.\",\n      \"method\": \"In vitro stimulation of primary HSCs with IL-22, p38 MAPK inhibitor, IL-22RA1 KO mice, two fibrosis models (TAA and CCl4), AhR/RORγt antagonists\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse, in vitro mechanistic (p38 MAPK), and two independent in vivo models in single study\",\n      \"pmids\": [\"30366940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-22 promotes allergic airway inflammation by enabling synergy with TNF-α (but not IL-17A) to elicit neutrophil-dominated airway inflammation and airway hyperresponsiveness; intranasal IL-22 + TNF-α recapitulated neutrophil recruitment in wild-type mice, while IL-22 deficiency increased IFN-γ production and reduced eosinophil/neutrophil recruitment.\",\n      \"method\": \"IL-22-/- mice, epicutaneous sensitization OVA model, intranasal cytokine instillation, cytokine neutralization antibodies, TH22-polarized T cell adoptive transfer\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mice, adoptive transfer, and cytokine instillation experiments with defined IL-22/TNF-α mechanistic synergy\",\n      \"pmids\": [\"29920352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-22 acts through Tyk2-STAT3 signaling in IECs; AhR in intestinal epithelial cells is required for optimal IL-22/STAT3 signaling — intestinal cell-specific AhR knockout reduces responsiveness to IL-22 in part by enhancing SOCS3 expression, which dampens STAT3 phosphorylation. Deletion of SOCS3 rescues pSTAT3 levels in AhR KO organoids.\",\n      \"method\": \"Intestinal cell-specific AhR KO mice and organoids, IL-22 stimulation, SOCS3 deletion, pSTAT3 measurement, AOM/DSS carcinogenesis model\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO, genetic rescue (SOCS3 deletion), and mechanistic epistasis in single rigorous study\",\n      \"pmids\": [\"34755534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-22 suppresses HSV-2 replication in human cervical epithelial cells through the IL-22 receptor complex (IL-22R1 and IL-10R2), activating JAK/STAT signaling via phosphorylation of STAT1 and STAT3, inducing IFN-stimulated genes (ISG15, ISG56, OAS-1, OAS-2, Mx2) and increasing tight junction proteins (ZO-1 and Occludin).\",\n      \"method\": \"IL-22 treatment of End1/E6E7 cells, Western blot for p-STAT1/p-STAT3, ISG expression assays, tight junction protein analysis, HSV-2 infection assays\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor identification, signaling pathway (JAK/STAT), and downstream gene induction characterized in single study\",\n      \"pmids\": [\"31344598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Runx1 and RORγt cooperatively upregulate IL-22 expression through a distal enhancer (CNS-32) located 32 kb upstream of the mouse Il22 promoter. Mutation of Runx1 and RORγt binding motifs in CNS-32 abrogated reporter activity; Runx1 overexpression promotes IL-22 via inducing RORγt and IL-23R; CBFB (Runx1 cofactor) knockdown limits IL-22 production.\",\n      \"method\": \"Reporter assay with CNS-32 enhancer element, binding motif mutagenesis, ChIP-seq for Runx1/RORγt occupancy and histone H4 acetylation, Runx1 overexpression, CBFB shRNA knockdown, Th22 differentiation assays\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP, reporter assay with mutagenesis, and gain/loss-of-function experiments in single rigorous study\",\n      \"pmids\": [\"31028121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-23 and IL-2 activation of STAT5 is required for optimal IL-22 production in ILC3s. IL-23 induces a STAT3-STAT5 complex that binds IL-22 promoter DNA elements in ILC3s. Mice lacking STAT5a or STAT5b are more susceptible to C. rodentium-mediated colitis with reduced IL-22 production.\",\n      \"method\": \"STAT5a/STAT5b KO mice, colitis model, ChIP for STAT3-STAT5 complex binding to IL-22 promoter, human and mouse colonic LP ILC3 stimulation assays\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP of STAT3-STAT5 at IL-22 promoter plus KO mouse validation across mouse and human cells\",\n      \"pmids\": [\"32332067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-6 and the aryl hydrocarbon receptor (AhR) transcription factor are required to polarize CD8+ T cells to an IL-22-producing Tc22 subset; Tc22 cells are highly cytolytic with a distinct cytokine profile and transcriptome relative to Tc1 cells.\",\n      \"method\": \"In vitro T cell polarization assays, AhR dependence assays, cytotoxicity assays, transcriptome analysis, tumor growth assays with polarized T cells\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro polarization with AhR requirement identified, single lab with multiple assays\",\n      \"pmids\": [\"31964625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Vitamin D3 (1,25(OH)2D3) inhibits IL-22 production in Th22 cells through the vitamin D receptor (VDR) binding to a repressive vitamin D response element (VDRE) identified in the il22 promoter. T cells with a mutated VDR do not show this 1,25(OH)2D3-mediated inhibition.\",\n      \"method\": \"Th22 cell polarization from naïve human CD4+ T cells, VDR-mutated T cells, luciferase reporter assay with il22 promoter VDRE, 1,25(OH)2D3 treatment\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reporter assay with defined VDRE plus VDR-mutant functional validation in human T cells, single rigorous study\",\n      \"pmids\": [\"34408754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nrf2 regulates IL-22 production in CD4+ T cells via the AhR pathway: Nrf2 binds to ARE motifs in the Ahr promoter to induce its transcription, and CDDO-Im-mediated Nrf2 activation induces IL-22 in a manner abolished by CD4-specific Ahr knockout and by an AhR antagonist. Nrf2 also binds an ARE repressor in the Rorc gene, inhibiting RORγt-dependent IL-17A transactivation.\",\n      \"method\": \"Nrf2 activator (CDDO-Im), CD4-specific Ahr KO mice, ChIP for Nrf2 binding to Ahr and Rorc ARE motifs, luciferase reporter assay for Ahr promoter, AhR antagonist CH-223191\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP, reporter assay, KO mice, and pharmacological validation converge on Nrf2→AhR→IL-22 axis\",\n      \"pmids\": [\"33648937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-22 unexpectedly signals on erythroid precursors, which express IL-22RA1. IL-22 blockade alleviates anemia in Riok2 haploinsufficient mice (a model of MDS del(5q)) and in wild-type mice; serum IL-22 is elevated in MDS del(5q) patients and in anemia of chronic kidney disease.\",\n      \"method\": \"Proteomic and transcriptomic analysis of erythroid precursors, IL-22RA1 expression on erythroid precursors, IL-22 blockade in Riok2f/+Vav1cre and WT mice, serum IL-22 quantification in patients\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — novel receptor expression identified, KO/blockade mouse models with in vivo functional validation, and human correlative data\",\n      \"pmids\": [\"33753942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-22 promotes intestinal crypt immunity via induction of phospho-STAT3 binding to the IL-18 gene promoter in epithelial cells, establishing an IL-22→STAT3→IL-18 signaling axis. IL-18 in turn promotes Lgr5+ stem cell expansion via Akt-Tcf4 signaling and IFNγ+ T cell responses. Epistasis experiments show IL-22-STAT3 acts upstream of IL-18-mediated barrier defense: IL-22 cannot restore parameters in Il-18-/- mice, but IL-18 restores parameters in Il-22-/- mice.\",\n      \"method\": \"Intestinal organoid culture, AIEC infection model, IL-22-/- and IL-18-/- mice, p-STAT3 ChIP on Il-18 promoter, cytokine rescue experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP, genetic epistasis with double KO, organoid assays, and in vivo infection model in single rigorous study\",\n      \"pmids\": [\"35169117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-22 signals in glioblastoma (GBM) cells via IL-22R1/IL-10R2 receptor complex to activate STAT3 and PI3K/AKT pathways, increasing Bcl-xL (anti-apoptotic) and decreasing p-ERK1/2, resulting in cell survival and proliferation. All 10 primary GBM cell lines tested expressed IL-22R subunits.\",\n      \"method\": \"RT-PCR, Western blot, confocal microscopy for IL-22R expression, BrdU proliferation assay, ELISA cell death assay, phospho-protein analysis in GBM lines\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor characterization plus downstream signaling validated across multiple cell lines, single lab\",\n      \"pmids\": [\"25793261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TNF induces IL-22BP (IL-22Ra2) expression in colonic dendritic cells via soluble TNF produced by IECs, thereby restricting IL-22/STAT3-mediated mucosal repair; anti-TNF therapy increases IL-22 bioavailability and IL-22-driven epithelial healing. Membrane-bound TNF from T cells perpetuates inflammation, while soluble TNF from IECs specifically drives IL-22BP induction in DCs.\",\n      \"method\": \"Humanized colitis model, TNF blockade experiments, IL-22BP induction in DCs, IL-22/STAT3-mediated repair assays, human monocyte-derived DC experiments, patient serum correlations\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — humanized model, DC cell experiments, mechanistic TNF→IL-22BP axis, and human clinical correlation in single study\",\n      \"pmids\": [\"35383266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-22 signals on proximal tubule cells (PTCs) via IL-22RA1 to amplify the DNA damage response (DDR), promoting cell death in AKI. PTCs are identified as a source of urinary IL-22; global IL-22 deletion and tubule-specific IL-22RA1 knockout both protect against cisplatin- or aristolochic acid-induced AKI by reducing DDR component expression and PTC cell death.\",\n      \"method\": \"Cisplatin and aristolochic acid AKI models, IL-22 global KO mice, tubule-specific IL-22RA1 KO (IL-22RA1ΔTub), primary PTC IL-22 stimulation, urinary IL-22 measurement\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — global and tissue-specific KO with two injury models, in vitro PTC signaling, novel PTC source and receptor identification\",\n      \"pmids\": [\"38054920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-22 resolves MASLD by signaling through its IEC receptor (not hepatocytes) to activate STAT3 and inhibit WNT-β-catenin signaling, thereby shrinking the absorptive enterocyte compartment and reducing macronutrient absorption. Exogenous IL-22 reverses hepatosteatosis, inflammation, fibrosis, and insulin resistance.\",\n      \"method\": \"Recombinant IL-22 administration in diet-induced MASLD mice, IEC-specific vs. hepatocyte-specific signaling analysis, STAT3 activation, WNT-β-catenin pathway assays\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific receptor targeting established, multiple disease endpoints reversed, defined STAT3/WNT-β-catenin mechanism\",\n      \"pmids\": [\"39317186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-22Ra1 signaling in MATH1+ intestinal cells (goblet and progenitor cells) is essential for maintaining mucosal barrier function and tissue regeneration. IL-22Ra1 signaling promotes mucin core-2 O-glycan extension by inducing B3GALT5 expression; adenoviral B3galt5 expression rescues Il22Ra1IEC mice from DSS colitis. B3GALT5 and Tn antigen expression are reduced in ulcerative colitis patient colon tissue.\",\n      \"method\": \"MATH1+ cell-specific Il22Ra1 conditional KO mice, DSS colitis model, adenoviral B3galt5 rescue, glycan analysis, organoid assays, human UC tissue analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO, adenoviral rescue, glycan mechanism defined, and human tissue validation in single rigorous study\",\n      \"pmids\": [\"38733584\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-22 is a cytokine that signals exclusively through the heterodimeric IL-22R1/IL-10R2 receptor complex on non-hematopoietic epithelial cells (skin, gut, liver, lung, kidney), activating JAK1/Tyk2-STAT3 as its primary downstream pathway, with additional activation of AKT, ERK, and p38 MAPK; its transcription is controlled by a regulatory circuit involving AhR, RORγt, Runx1, STAT3, STAT5, NF-κB p65, and is repressed by vitamin D receptor binding a repressive VDRE in the il22 promoter; IL-22 drives epithelial proliferation, anti-apoptosis (via Bcl-xL), antimicrobial peptide production, goblet cell hyperplasia and mucin O-glycosylation, intestinal barrier repair (through an IL-22→STAT3→IL-18→Akt-Tcf4 axis), acute-phase responses in liver (via C3, fibrinogen, SAA induction), and tissue-specific pathological effects including HSC-mediated liver fibrosis (via TGF-β/p38 MAPK), SMC dedifferentiation in atherosclerosis, and erythroid suppression via unexpected IL-22RA1 expression on erythroid precursors; its bioavailability is antagonized by the soluble decoy receptor IL-22BP (IL-22RA2), which exists in three human isoforms with distinct inhibitory potencies regulated by TLR2 and retinoic acid signaling in myeloid cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL-22 is a cytokine that mediates directional communication from the immune system to epithelial tissues, signaling through an IL-22R1/IL-10R2 receptor complex whose expression is restricted to non-hematopoietic epithelial cells while being absent on immune cells [#2, #20]. Receptor engagement activates a JAK family kinase Tyk2 to drive STAT3 phosphorylation, with intestinal epithelial AhR sustaining this response by limiting SOCS3-mediated STAT3 dampening [#12, #19]; additional STAT1, AKT, and ERK arms are engaged in a tissue- and context-dependent manner [#13, #20, #28]. Downstream of STAT3, IL-22 promotes epithelial proliferation, anti-apoptosis, and antimicrobial defense, and in the intestine it enforces barrier integrity through a STAT3-driven IL-18 axis that expands Lgr5+ stem cells via Akt-Tcf4 and through induction of B3GALT5-dependent mucin core-2 O-glycosylation and goblet cell hyperplasia [#27, #32, #6]. Systemically, hepatic IL-22-STAT3 signaling drives acute-phase and complement (C3) responses that promote antimicrobial opsonization and tissue protection [#4, #9, #7]. IL-22 transcription is governed by a multifactorial circuit in which ROR\\u03b3t and Runx1/CBFB act through a distal CNS-32 enhancer, AhR, STAT3, STAT5, and NF-\\u03baB p65 promote expression in T cells and innate lymphoid cells, and signals including IL-21, IL-23, IL-2, IL-6, Nrf2, and retinoic acid feed into this network, while vitamin D receptor binding a repressive VDRE shuts it down [#21, #5, #16, #22, #25, #24]. IL-22 bioavailability is set by the soluble decoy IL-22BP (IL-22RA2), whose three splice isoforms differ in potency and whose induction is controlled by TLR2, retinoic acid, and TNF signaling in myeloid and dendritic cells [#14, #29]. Beyond protective roles, IL-22 has context-dependent pathological effects, including p38 MAPK-dependent enhancement of TGF-\\u03b2 signaling in hepatic stellate cell fibrosis, smooth muscle cell dedifferentiation in atherosclerosis, amplification of the DNA damage response in proximal tubule injury, suppression of erythropoiesis via IL-22RA1 on erythroid precursors, and promotion of tumor cell survival and invasion [#17, #11, #30, #26, #28].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing the genomic structure and a cis-regulatory element answered where IL-22 sits in the genome and how its expression is first controlled, linking it to IL-9-induced transcription.\",\n      \"evidence\": \"Genomic sequencing, chromosomal mapping, and luciferase reporter assay of the IL-TIF promoter\",\n      \"pmids\": [\"11197690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the transcription factors binding the IL-9-responsive element\", \"No protein-level functional characterization\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The crystal structure defined the cytokine fold and mapped surfaces corresponding to IL-22R1 and IL-10R2 contacts, providing the structural basis for receptor recognition.\",\n      \"evidence\": \"X-ray crystallography at 2.6 \\u00c5 of insect-cell-expressed IL-22 with structural comparison across monomers\",\n      \"pmids\": [\"15983417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal structure with the receptor heterodimer\", \"Functional consequence of the main-chain differences at binding sites not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Restriction of IL-22 receptor expression to epithelial tissues and the central role of STAT3 established the directionality of IL-22 signaling from immune cells to tissue and distinguished its effects from IL-17.\",\n      \"evidence\": \"Immunohistochemistry, gene array, and organotypic skin model with keratinocyte differentiation readouts\",\n      \"pmids\": [\"19016525\", \"18684158\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"JAK kinase mediating STAT3 activation not yet defined\", \"Mechanism of receptor exclusion from immune cells unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Systemic IL-22 delivery revealed a hepatic acute-phase program, showing IL-22 acts beyond local epithelia to modulate coagulation factors and serum proteins.\",\n      \"evidence\": \"Adenoviral and recombinant IL-22 administration in mice with hematological and biochemical analyses\",\n      \"pmids\": [\"20870942\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish hepatic STAT3 dependence directly\", \"Physiological versus pharmacological relevance of systemic doses unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defining the IL-21\\u2192STAT3\\u2192AhR and ROR\\u03b3t pathways and goblet cell induction answered how IL-22 is transcriptionally induced in T cells and how it executes mucosal anti-helminth defense.\",\n      \"evidence\": \"T cell differentiation, il22 promoter epigenetic/AhR analysis, ILC-deficient colitis model, and IL-22-KO helminth infection models\",\n      \"pmids\": [\"24796415\", \"24130494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of T cells versus ILCs to IL-22 in vivo not fully resolved\", \"Goblet cell transcriptional targets downstream of IL-22 not detailed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Tissue-specific genetic studies in liver, kidney, and lung dissected dual protective and detrimental hepatic STAT3 outcomes and a hepatic C3-complement mechanism, defining IL-22 as an organ-protective and regenerative cytokine.\",\n      \"evidence\": \"Liver-specific STAT3 KO, Cyp2E1 KO, hepatic-specific Il22ra1 KO, IL-22-KO kidney injury models, and reconstitution/blockade experiments\",\n      \"pmids\": [\"25063867\", \"24459235\", \"27456484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants switching IL-22 between protective and toxic outcomes not defined\", \"Cell-of-origin of IL-22 in each tissue not fully resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of Tyk2 as the JAK mediating epithelial STAT3 activation, plus pathological signaling in cancer and smooth muscle, established the proximal signaling kinase and the context-dependent breadth of IL-22 effects.\",\n      \"evidence\": \"IEC-specific Tyk2 KO with rescue and infection/colitis models, IL-22R1 knockdown in gastric cancer cells, and IL-22-/-ApoE-/- atherosclerosis model\",\n      \"pmids\": [\"26432894\", \"25120745\", \"26298743\", \"26130064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Tyk2 is the dominant JAK in non-intestinal tissues not tested\", \"AKT/ERK arm activation mechanisms in tumor cells incompletely defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Functional characterization of the three IL-22BP isoforms and their myeloid regulation defined the decoy rheostat controlling IL-22 bioavailability, and identification of ROR\\u03b3t/AhR-dependent neutrophil production added a cellular source.\",\n      \"evidence\": \"Isoform-specific inhibition and secretion assays with TLR2/retinoic acid myeloid activation, and neutrophil mTOR-ROR\\u03b3t/AhR pathway with inhibitor epistasis\",\n      \"pmids\": [\"27678220\", \"27067005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution of each IL-22BP isoform not separately measured\", \"Structural basis of differential isoform potency unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"ChIP and reporter evidence that NF-\\u03baB p65 binds the IL22 promoter in ILC3s, with IL-18/IL-15 cooperation, expanded the transcriptional circuit controlling IL-22 in innate lymphoid cells.\",\n      \"evidence\": \"ChIP and luciferase reporter assays, NF-\\u03baB inhibition, and cytokine stimulation of human ILC3s\",\n      \"pmids\": [\"28842466\", \"29980608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of NF-\\u03baB with STAT and AhR inputs on the promoter not mapped\", \"Dexamethasone target genes beyond NF-\\u03baB modulation not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defining a p38 MAPK-dependent profibrotic role in hepatic stellate cells and TNF-\\u03b1 synergy in airway inflammation established that IL-22 can be pathogenic through tissue-specific and cytokine-context effects.\",\n      \"evidence\": \"IL-22RA1 KO with two fibrosis models and HSC p38 inhibition, plus IL-22-/- mice with intranasal cytokine and adoptive transfer airway models\",\n      \"pmids\": [\"30366940\", \"29920352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How epithelial STAT3 versus HSC p38 outputs are partitioned not resolved\", \"Mechanism of IL-22/TNF-\\u03b1 synergy at the receptor/signaling level not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Epithelial AhR was shown to sustain IL-22/STAT3 signaling by restraining SOCS3, and the IL-22R complex was shown to drive antiviral ISG induction and barrier proteins, refining how responsiveness to IL-22 is calibrated and expanding its antiviral role.\",\n      \"evidence\": \"Intestinal AhR KO organoids with SOCS3 deletion rescue and pSTAT3 readouts, and IL-22 stimulation of cervical epithelial cells with ISG/tight junction assays\",\n      \"pmids\": [\"34755534\", \"31344598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which AhR represses SOCS3 not defined\", \"STAT1 versus STAT3 contributions to antiviral ISGs not separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of the CNS-32 enhancer bound cooperatively by Runx1/CBFB and ROR\\u03b3t defined a distal cis-regulatory module driving IL-22 transcription.\",\n      \"evidence\": \"Reporter assay with motif mutagenesis, ChIP-seq for Runx1/ROR\\u03b3t occupancy, and Runx1 gain-of-function with CBFB knockdown\",\n      \"pmids\": [\"31028121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between CNS-32 and proximal promoter elements not integrated\", \"Human conservation of CNS-32 function not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"STAT5 (downstream of IL-23/IL-2) forming a STAT3-STAT5 complex on the IL-22 promoter, and AhR-dependent Tc22 CD8 polarization, further resolved the signaling inputs and cellular sources generating IL-22.\",\n      \"evidence\": \"STAT5a/STAT5b KO colitis models with ChIP of the STAT3-STAT5 complex, and in vitro AhR-dependent CD8 polarization with cytotoxicity and tumor assays\",\n      \"pmids\": [\"32332067\", \"31964625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly of the STAT3-STAT5 complex unknown\", \"In vivo significance of Tc22 cells not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Vitamin D/VDR repression via a promoter VDRE, Nrf2-driven induction of AhR, and an unexpected IL-22RA1-dependent effect on erythroid precursors expanded both the repressive transcriptional control and the target cell repertoire of IL-22.\",\n      \"evidence\": \"VDR-mutant Th22 cells with VDRE reporter, Nrf2 activator/CD4 AhR KO with ARE ChIP, and erythroid precursor profiling with IL-22 blockade in mouse anemia models and patient serum\",\n      \"pmids\": [\"34408754\", \"33648937\", \"33753942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether VDR and Nrf2 inputs operate in the same cells not addressed\", \"Downstream signaling of IL-22 in erythroid precursors not detailed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"An IL-22\\u2192STAT3\\u2192IL-18\\u2192Akt-Tcf4 axis and a TNF\\u2192IL-22BP decoy circuit defined how IL-22 directs stem cell-driven barrier defense and how its activity is suppressed during inflammation, with direct therapeutic relevance to anti-TNF response.\",\n      \"evidence\": \"Organoid/AIEC infection with IL-22-/-/IL-18-/- epistasis and p-STAT3 ChIP on Il-18, plus humanized colitis with DC IL-22BP induction and patient correlation; GBM receptor signaling characterized in parallel\",\n      \"pmids\": [\"35169117\", \"35383266\", \"25793261\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How soluble versus membrane TNF differentially engage DCs mechanistically not fully resolved\", \"Generality of the IL-18 axis outside the intestine untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstration that IL-22 amplifies the DNA damage response in proximal tubule cells to promote cell death in AKI clarified a damaging, injury-context role distinct from its regenerative effects.\",\n      \"evidence\": \"Cisplatin/aristolochic acid AKI in global IL-22 KO and tubule-specific IL-22RA1 KO mice with primary PTC stimulation and urinary IL-22 measurement\",\n      \"pmids\": [\"38054920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between IL-22R signaling and DDR component induction not defined\", \"Reconciliation with earlier protective kidney regeneration role not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing IL-22 resolves MASLD through IEC (not hepatocyte) STAT3 signaling that inhibits WNT-\\u03b2-catenin to shrink the absorptive compartment, and through MATH1+ cell B3GALT5-dependent mucin glycosylation, refined the target cell and effector mechanisms of metabolic and barrier protection.\",\n      \"evidence\": \"Recombinant IL-22 in diet-induced MASLD with IEC versus hepatocyte signaling analysis, and MATH1+ cell-specific Il22Ra1 KO with adenoviral B3galt5 rescue, glycan analysis, and human UC tissue\",\n      \"pmids\": [\"39317186\", \"38733584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IL-22-STAT3 inhibits WNT-\\u03b2-catenin mechanistically not defined\", \"Whether enterocyte-shrinking mechanism applies in human metabolic disease untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"What determines the switch between IL-22's protective/regenerative and pathological/pro-death outputs in the same epithelial tissue remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unifying model for context-dependent IL-22 outcomes\", \"Receptor-proximal signaling differences between protective and damaging contexts undefined\", \"Therapeutic window for IL-22 agonism versus blockade unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2, 20, 28]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 12, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [4, 14, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 12, 20]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 9, 14]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 16, 21, 22, 24, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IL22RA1\", \"IL10R2\", \"IL22RA2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}