Affinage

IL22

Interleukin-22 · UniProt Q9GZX6

Round 2 corrected
Length
179 aa
Mass
20.0 kDa
Annotated
2026-04-28
130 papers in source corpus 38 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2000 High

    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

    PMID:10657629 PMID:10875937 PMID:10954742 PMID:11035029

    Open questions at the time
    • 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
  2. 2002 High

    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

    PMID:12087100

    Open questions at the time
    • Kinase responsible for STAT3 Ser727 phosphorylation downstream of IL-22 was not identified
    • Contribution of individual MAPK branches to specific gene programs remained unclear
  3. 2004 High

    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

    PMID:15122762

    Open questions at the time
    • Whether STAT3-independent pathways contribute to hepatoprotection was not tested
    • Duration and dose-dependence of protective versus potentially oncogenic STAT3 activation were unexplored
  4. 2005 High

    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

    PMID:16143135

    Open questions at the time
    • 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
  5. 2006 High

    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

    PMID:16537974

    Open questions at the time
    • In vivo validation of PI3K-dependent migration in wound healing was lacking
    • Receptor expression regulation in primary human IECs was not confirmed
  6. 2008 High

    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

    PMID:18264110 PMID:18978771

    Open questions at the time
    • 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
  7. 2011 High

    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

    PMID:21600206 PMID:21674558

    Open questions at the time
    • Direct AhR binding to the IL22 promoter was not demonstrated in this study
    • Thresholds distinguishing protective versus tumorigenic IL-22/STAT3 activity were undefined
  8. 2013 High

    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

    PMID:24130494

    Open questions at the time
    • 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
  9. 2014 High

    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

    PMID:24796415 PMID:24816405 PMID:25063867 PMID:25208211 PMID:35169117

    Open questions at the time
    • 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
  10. 2015 High

    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

    PMID:26432894 PMID:27456484

    Open questions at the time
    • Whether JAK1 is equally required in IECs was not tested in conditional models
    • Whether C3 induction is STAT3-dependent was not directly confirmed
  11. 2016 High

    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

    PMID:27678220

    Open questions at the time
    • Structural basis for differential IL-22 binding affinity of isoforms was not resolved
    • In vivo isoform-specific functions in disease models were not tested
  12. 2017 High

    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

    PMID:28583370 PMID:28842466

    Open questions at the time
    • 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
  13. 2020 High

    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

    PMID:31932715 PMID:32901017

    Open questions at the time
    • Specific SCFAs (butyrate vs propionate) contributing most to HIF1α-driven IL-22 were not resolved
    • How IL-22 shapes microbiome composition mechanistically is unknown
  14. 2022 High

    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

    PMID:35383266

    Open questions at the time
    • 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
  15. 2024 High

    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

    PMID:39317186

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 8 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 5
Pathway
R-HSA-168256 Immune System 11 R-HSA-162582 Signal Transduction 7 GO:0140110 transcription regulator activity 6 R-HSA-1500931 Cell-Cell communication 3 R-HSA-1643685 Disease 3
Partners
IL10RBIL22RA1IL22RA2JAK1STAT3TYK2

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 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. Receptor binding assays, STAT activation assays in cell lines, functional cytokine production assays The Journal of biological chemistry High 10875937
2000 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. cDNA subtraction cloning, recombinant protein stimulation, Western blot for STAT activation, antibody blockade Journal of immunology (Baltimore, Md. : 1950) High 10657629
2000 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. COS cell expression of receptor chains, hamster cell reconstitution, radiolabeled IL-22 cross-linking, intracellular domain swap experiments The Journal of biological chemistry High 11035029
2000 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. cDNA cloning, STAT activation assays, ELISA for acute phase proteins, antibody neutralization Proceedings of the National Academy of Sciences of the United States of America High 10954742
2002 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. Immunoblot with phospho-specific antibodies, kinase-specific inhibitors, STAT3 S727A mutant overexpression, transcriptional reporter assay The Journal of biological chemistry High 12087100
2003 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. Genomic library screening, RT-PCR, binding assays, STAT3 activation assays, ROS measurement Genes and immunity High 12700595
2004 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. Genomic sequence analysis, RT-PCR, quantitative expression analysis Genes and immunity Medium 15201862
2004 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. Expression analysis, receptor characterization, functional cytokine assays International immunopharmacology Medium 15120651
2004 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. Neutralizing antibody in vivo, recombinant cytokine injection, stable overexpression, STAT3 inhibition, Western blot for downstream targets Hepatology (Baltimore, Md.) High 15122762
2005 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. cDNA microarray, Northern blot, ELISA, EMSA for NF-κB/AP-1, pharmacological inhibitors Gastroenterology High 16143135
2006 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. Western blot for signaling pathways, proliferation assay, PI3K inhibitor treatment, wounding/migration assay, RT-PCR American journal of physiology. Gastrointestinal and liver physiology High 16537974
2008 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. Mouse infection model with IL-22 and IL-17A neutralization/KO, epithelial barrier assays, chemokine measurement Nature medicine High 18264110
2008 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. Cell isolation and characterization, cytokine stimulation assays, in vitro epithelial cell co-culture, in vivo bacterial infection model Nature High 18978771
2011 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. In vitro cytokine production assays, multiple in vivo colitis models with AhR agonist/antagonist, IL-22 neutralizing antibody epistasis experiment Gastroenterology High 21600206
2013 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. IL-22 KO mouse infection model, ex vivo and in vitro epithelial stimulation, goblet cell marker quantification PLoS pathogens High 24130494
2014 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. IL-22 KO mice, IL-22 blockade, TLR4 blockade, cell depletion/reconstitution experiments, in vitro tubular cell recovery assay Journal of the American Society of Nephrology : JASN High 24459235
2014 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. Patient tissue analysis, mouse colon cancer model, STAT3 activation assays, DOT1L expression analysis, stem cell gene expression, CCR6 KO experiments Immunity High 24816405
2014 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. Liver-specific STAT3 KO, IL-22 transgenic mice, IL-22 adenovirus treatment, CYP2E1 KO, HNF-1α expression analysis Journal of immunology (Baltimore, Md. : 1950) High 25063867
2014 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. In vitro T cell stimulation, STAT3 activation and chromatin analysis, AhR interaction assays, in vivo colitis model in ILC-deficient mice Nature communications High 24796415
2015 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. Conditional Tyk2 KO mice, primary IEC stimulation with IL-22, pSTAT3 assays, colitis model with Citrobacter rodentium Journal of immunology (Baltimore, Md. : 1950) High 26432894
2015 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. Hepatic-specific IL-22Ra1 KO mice, recombinant IL-22 administration, C3 expression assays, opsonic killing assays Journal of immunology (Baltimore, Md. : 1950) High 27456484
2016 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. Isoform-specific expression constructs, secretion assays, IL-22 STAT3 reporter assays, TLR2 and retinoic acid stimulation of myeloid cells Science signaling High 27678220
2017 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. NF-κB p65 ChIP assay at IL22 promoter, ILC3 proliferation assays, IL-22 production measurement, in situ proximity analysis in tonsil tissue Journal of immunology (Baltimore, Md. : 1950) High 28842466
2014 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. Primary keratinocyte cultures, Th22 cell supernatant stimulation, wound healing assay, neutralizing antibody experiments The Journal of clinical investigation High 19920355
2011 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. IL-22 KO mouse HCC model, STAT3 phosphorylation assays, downstream target gene expression, in vivo subrenal cotransplantation experiments Hepatology (Baltimore, Md.) High 21674558
2014 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. ChIP (pSTAT3 at Il-18 promoter), intestinal organoid culture, IL-22 and IL-18 KO mice, AIEC infection model, genetic epistasis experiments Nature communications High 35169117
2018 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. Ileal mouse organoid screen, single-cell RNA sequencing for Il22ra1 expression, ISC serial passaging assay, IL-22 transgenic mouse analysis Cellular and molecular gastroenterology and hepatology High 30364840
2014 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. Keratinocyte stimulation with recombinant IL-22, Western blot for phospho-MAPK, qRT-PCR, CCK-8 proliferation assay, C/EBPα siRNA knockdown Molecular medicine reports Medium 32945375
2014 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. Luciferase reporter assay, STAT3 ChIP at miR-197 promoter, miR-197 overexpression, migration assays, IL22RA1 3'UTR targeting validation PloS one High 25208211
2017 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. T-cell cultures with PGE2 and receptor-specific agonists/antagonists, T cell-specific EP4 KO mice, in vivo hapten sensitization model The Journal of allergy and clinical immunology High 28583370
2020 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. GPR41 KO, HDAC inhibitor studies, ChIP for HIF1α at Il22 promoter, mTOR/STAT3 inhibition, histone modification assays Nature communications High 32901017
2020 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. Il10-/-Il22-/- double KO genetic model, histology, antimicrobial gene expression, 16S microbiome analysis Mucosal immunology High 31932715
2019 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. MNV infection model, IFN-I signaling analysis, IL-22 KO mice, ILC characterization, STAT3 signaling assays Nature microbiology High 31182797
2022 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. 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 Mucosal immunology High 35383266
2024 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. Recombinant IL-22 treatment, IEC-specific receptor studies, STAT3 and WNT-β-catenin signaling analysis, intestinal morphometric analysis, diet-induced MASLD mouse model Cell metabolism High 39317186
2010 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. IL-17RA KO mice, IL-22 neutralization, Candida albicans infection model, epithelial integrity assays Mucosal immunology High 20445503
2016 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. T cell polarization assays, SCC cell invasion/migration assays, UV-induced SCC mouse model with anti-IL-22 antibody treatment JCI insight Medium 27699266
2019 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. Flow cytometry on lesional keratinocytes, cytokine treatment of normal keratinocytes, colony-forming efficiency assay The Journal of investigative dermatology Medium 30684548

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 3725 23128233
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2007 IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 1476 17581588
2008 A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 1061 18978771
2008 IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nature medicine 962 18264110
2020 COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. Cardiovascular research 943 32352535
2020 Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity. Nature communications 826 32901017
2009 Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. The Journal of clinical investigation 807 19920355
2015 Interleukin-22: immunobiology and pathology. Annual review of immunology 730 25706098
2011 Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 549 21600206
2009 Anti-inflammatory and pro-inflammatory roles of TGF-beta, IL-10, and IL-22 in immunity and autoimmunity. Current opinion in pharmacology 526 19481975
2004 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. Hepatology (Baltimore, Md.) 497 15122762
2009 Circulating Th17, Th22, and Th1 cells are increased in psoriasis. The Journal of investigative dermatology 495 20032993
2006 IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. American journal of physiology. Gastrointestinal and liver physiology 472 16537974
2000 Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R. The Journal of biological chemistry 441 10875937
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2009 Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis and rheumatism 437 19479869
2002 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. The Journal of biological chemistry 407 12087100
2005 Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology 400 16143135
2000 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. Journal of immunology (Baltimore, Md. : 1950) 399 10657629
2013 IL-22, not simply a Th17 cytokine. Immunological reviews 371 23405899
2020 The role of IL-22 in intestinal health and disease. The Journal of experimental medicine 367 32997932
2009 Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nature genetics 336 19122664
2014 CX₃CR1⁺ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22. The Journal of experimental medicine 334 25024136
2000 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. The Journal of biological chemistry 330 11035029
2014 Epidermal Th22 and Tc17 cells form a localized disease memory in clinically healed psoriasis. Journal of immunology (Baltimore, Md. : 1950) 329 24610014
2014 IL-22(+)CD4(+) T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L. Immunity 324 24816405
2000 Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor. Proceedings of the National Academy of Sciences of the United States of America 292 10954742
2003 The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. Genome research 285 12975309
2011 Recent advances in IL-22 biology. International immunology 265 21393631
2010 Overrepresentation of IL-17A and IL-22 producing CD8 T cells in lesional skin suggests their involvement in the pathogenesis of psoriasis. PloS one 262 21124836
2011 Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology (Baltimore, Md.) 259 21674558
2007 The molecular basis of IL-21-mediated proliferation. Blood 256 17234735
2005 Interleukin-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn's disease. Gastroenterology 243 15765404
2008 IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype. Proceedings of the National Academy of Sciences of the United States of America 229 19088203
2010 IL-22 defines a novel immune pathway of antifungal resistance. Mucosal immunology 219 20445503
2010 IL-17 and IL-22: siblings, not twins. Trends in immunology 202 20691634
2017 Clinical importance of IL-22 cascade in IBD. Journal of gastroenterology 183 29075900
2014 Cytokine-Mediated Regulation of Plasma Cell Generation: IL-21 Takes Center Stage. Frontiers in immunology 172 24600453
2003 IL-21 induces the apoptosis of resting and activated primary B cells. Journal of immunology (Baltimore, Md. : 1950) 161 12682241
2014 Directing traffic: IL-17 and IL-22 coordinate pulmonary immune defense. Immunological reviews 158 24942687
2019 Clinical significance and immunobiology of IL-21 in autoimmunity. Journal of autoimmunity 155 30773373
2018 Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab. The Journal of allergy and clinical immunology 148 30121291
2009 IL-21 mediates suppressive effects via its induction of IL-10. Journal of immunology (Baltimore, Md. : 1950) 147 19234181
2016 IL-21 Signaling in Immunity. F1000Research 144 26966515
2014 IL-21 induces IL-22 production in CD4+ T cells. Nature communications 136 24796415
2007 IL-21 regulates experimental colitis by modulating the balance between Treg and Th17 cells. European journal of immunology 136 17918200
2013 The role of IL-22 and Th22 cells in human skin diseases. Journal of dermatological science 135 23746568
2009 IL-21: an executor of B cell fate. Journal of immunology (Baltimore, Md. : 1950) 125 19201828
2013 IL-22 mediates goblet cell hyperplasia and worm expulsion in intestinal helminth infection. PLoS pathogens 122 24130494
2014 Toll-like receptor 4-induced IL-22 accelerates kidney regeneration. Journal of the American Society of Nephrology : JASN 121 24459235
2006 IL-21 inhibits IFN-gamma production in developing Th1 cells through the repression of Eomesodermin expression. Journal of immunology (Baltimore, Md. : 1950) 117 16951332
2005 Differential effects of IL-21 during initiation and progression of autoimmunity against neuroantigen. Journal of immunology (Baltimore, Md. : 1950) 110 15728477
2012 Healing of intestinal inflammation by IL-22. Inflammatory bowel diseases 108 22359410
2015 Opposing roles of STAT1 and STAT3 in IL-21 function in CD4+ T cells. Proceedings of the National Academy of Sciences of the United States of America 107 26170288
2010 Redundant and pathogenic roles for IL-22 in mycobacterial, protozoan, and helminth infections. Journal of immunology (Baltimore, Md. : 1950) 107 20220096
2010 Regulation of human Th9 differentiation by type I interferons and IL-21. Immunology and cell biology 104 20421880
2004 IL-22, a Th1 cytokine that targets the pancreas and select other peripheral tissues. International immunopharmacology 103 15120651
2008 Autocrine regulation of IL-21 production in human T lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 99 18209077
2010 Distinct roles of IL-22 in human psoriasis and inflammatory bowel disease. Cytokine & growth factor reviews 96 21106435
2014 T cell-derived interleukin (IL)-21 promotes brain injury following stroke in mice. The Journal of experimental medicine 95 24616379
2015 Interleukin (IL)-21 promotes intestinal IgA response to microbiota. Mucosal immunology 93 25586558
2013 IL-21-producing Th cells in immunity and autoimmunity. Journal of immunology (Baltimore, Md. : 1950) 86 24058193
2011 IL-22, but not IL-17, dominant environment in cutaneous T-cell lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research 85 22048239
2022 IL-22 initiates an IL-18-dependent epithelial response circuit to enforce intestinal host defence. Nature communications 84 35169117
2019 IFN-I and IL-22 mediate protective effects of intestinal viral infection. Nature microbiology 84 31182797
2017 IL-18 Drives ILC3 Proliferation and Promotes IL-22 Production via NF-κB. Journal of immunology (Baltimore, Md. : 1950) 82 28842466
2014 IL-22, cell regeneration and autoimmunity. Cytokine 73 25467639
2021 New developments implicating IL-21 in autoimmune disease. Journal of autoimmunity 70 34224936
2007 Overexpression of IL-21 promotes massive CD8+ memory T cell accumulation. European journal of immunology 70 17918202
2018 IL22 Inhibits Epithelial Stem Cell Expansion in an Ileal Organoid Model. Cellular and molecular gastroenterology and hepatology 69 30364840
2012 IL-15 positively regulates IL-21 production in celiac disease mucosa. Mucosal immunology 68 22785229
2007 IL-21 promotes T lymphocyte survival by activating the phosphatidylinositol-3 kinase signaling cascade. Journal of leukocyte biology 65 17554014
2013 IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection. PLoS pathogens 64 23696736
2019 IL-17 and IL-22 Promote Keratinocyte Stemness in the Germinative Compartment in Psoriasis. The Journal of investigative dermatology 63 30684548
2020 The development of colitis in Il10-/- mice is dependent on IL-22. Mucosal immunology 60 31932715
2015 Advances in IL-21 biology - enhancing our understanding of human disease. Current opinion in immunology 60 25801685
2003 Cloning and characterization of mouse IL-22 binding protein. Genes and immunity 59 12700595
2016 IL-21 Enhances Natural Killer Cell Response to Cetuximab-Coated Pancreatic Tumor Cells. Clinical cancer research : an official journal of the American Association for Cancer Research 58 27435400
2017 Prostaglandin E2 stimulates adaptive IL-22 production and promotes allergic contact dermatitis. The Journal of allergy and clinical immunology 53 28583370
2014 Acute and chronic effects of IL-22 on acetaminophen-induced liver injury. Journal of immunology (Baltimore, Md. : 1950) 53 25063867
2004 Cloning of murine IL-22 receptor alpha 2 and comparison with its human counterpart. Genes and immunity 53 15201862
2009 IL-21: roles in immunopathology and cancer therapy. Tissue antigens 52 19845910
2022 Role of IL-22 in homeostasis and diseases of the skin. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 51 35316548
2018 IL-21 Selectively Protects CD62L+ NKT Cells and Enhances Their Effector Functions for Adoptive Immunotherapy. Journal of immunology (Baltimore, Md. : 1950) 51 30111631
2015 Pathogen Resistance Mediated by IL-22 Signaling at the Epithelial-Microbiota Interface. Journal of molecular biology 50 26497621
2014 The crosstalk between IL-22 signaling and miR-197 in human keratinocytes. PloS one 49 25208211
2016 Critical Role of IL-22/IL22-RA1 Signaling in Pneumococcal Pneumonia. Journal of immunology (Baltimore, Md. : 1950) 46 27456484
2011 Key role for IL-21 in experimental autoimmune uveitis. Proceedings of the National Academy of Sciences of the United States of America 46 21593413
2017 Paeoniflorin suppressed IL-22 via p38 MAPK pathway and exerts anti-psoriatic effect. Life sciences 45 28456711
2015 Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis. Journal of immunology (Baltimore, Md. : 1950) 43 26432894
2022 IL-21 has a critical role in establishing germinal centers by amplifying early B cell proliferation. EMBO reports 42 35801309
2008 IL-21 limits peripheral lymphocyte numbers through T cell homeostatic mechanisms. PloS one 42 18773086
2007 IL-21 induces inhibitor of differentiation 2 and leads to complete abrogation of anaphylaxis in mice. Journal of immunology (Baltimore, Md. : 1950) 42 18056403
2001 Cytokines: IL-21 joins the gamma(c)-dependent network? Current biology : CB 42 11267886
2020 IL6 Induces an IL22+ CD8+ T-cell Subset with Potent Antitumor Function. Cancer immunology research 39 31964625
2015 IL10R2 Overexpression Promotes IL22/STAT3 Signaling in Colorectal Carcinogenesis. Cancer immunology research 38 26130064
2013 Genetic variants of the IL22 promoter associate to onset of psoriasis before puberty and increased IL-22 production in T cells. The Journal of investigative dermatology 38 24390134
2016 Cyclosporine A immunosuppression drives catastrophic squamous cell carcinoma through IL-22. JCI insight 37 27699266
2011 IL-21 promotes skin recruitment of CD4(+) cells and drives IFN-γ-dependent epidermal hyperplasia. Journal of immunology (Baltimore, Md. : 1950) 34 21441456
2024 IL-22 resolves MASLD via enterocyte STAT3 restoration of diet-perturbed intestinal homeostasis. Cell metabolism 33 39317186
2016 IL-22 Restrains Tapeworm-Mediated Protection against Experimental Colitis via Regulation of IL-25 Expression. PLoS pathogens 32 27055194
2015 A pathogenetic role for IL-21 in primary Sjögren syndrome. Nature reviews. Rheumatology 32 25584898
2018 The role of IL-22 in the resolution of sterile and nonsterile inflammation. Clinical & translational immunology 31 29713472
2015 Increased IL-21 expression in chronic rhinosinusitis with nasalpolyps. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 31 25495679
2017 IL-21 promotes the development of a CD73-positive Vγ9Vδ2 T cell regulatory population. Oncoimmunology 29 29296543
2012 Implication of IL-2/IL-21 region in systemic sclerosis genetic susceptibility. Annals of the rheumatic diseases 29 23172754
2007 Role of IL-21 in immune-regulation and tumor immunotherapy. Cancer immunology, immunotherapy : CII 29 17447063
2019 Interleukin (IL)-21 in Inflammation and Immunity During Parasitic Diseases. Frontiers in cellular and infection microbiology 28 31867283
2022 TNF hampers intestinal tissue repair in colitis by restricting IL-22 bioavailability. Mucosal immunology 27 35383266
2014 Exploring the IL-21-STAT3 axis as therapeutic target for Sézary syndrome. The Journal of investigative dermatology 26 24756111
2013 Salivary IL-21 and IgA responses to a competitive match in elite basketball players. Biology of sport 26 24744495
2020 Evaluation of the effects of IL‑22 on the proliferation and differentiation of keratinocytes in vitro. Molecular medicine reports 24 32945375
2016 Human IL-22 binding protein isoforms act as a rheostat for IL-22 signaling. Science signaling 24 27678220
2013 Serum IL-21 levels decrease with glucocorticoid treatment in myasthenia gravis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 24 23708911
2012 Cerebrospinal fluid IL-21 levels in Neuromyelitis Optica and multiple sclerosis. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 24 23041403
2023 Current Knowledge of Th22 Cell and IL-22 Functions in Infectious Diseases. Pathogens (Basel, Switzerland) 23 36839448
2016 Dynamic Long-Range Chromatin Interaction Controls Expression of IL-21 in CD4+ T Cells. Journal of immunology (Baltimore, Md. : 1950) 23 27067007
2016 Natural allelic variation of the IL-21 receptor modulates ischemic stroke infarct volume. The Journal of clinical investigation 23 27400126
2008 IL-21 promotes survival and maintains a naive phenotype in human CD4+ T lymphocytes. International immunology 23 18556671
2020 IL-22 Paucity in APECED Is Associated With Mucosal and Microbial Alterations in Oral Cavity. Frontiers in immunology 22 32477345
2018 Evaluating IL-21 as a Potential Therapeutic Target in Crohn's Disease. Gastroenterology research and practice 22 29849593
2018 IL-22 sustains epithelial integrity in progressive kidney remodeling and fibrosis. Physiological reports 22 30156011
2020 IL-21 Signaling in the Tumor Microenvironment. Advances in experimental medicine and biology 21 32060889
2017 IL-21 Is Increased in Nasal Polyposis and after Stimulation with Staphylococcus aureus Enterotoxin B. International archives of allergy and immunology 21 29131072
2013 The cellular source and target of IL-21 in K/BxN autoimmune arthritis. Journal of immunology (Baltimore, Md. : 1950) 21 23960240
2012 Psoriasis, from pathogenesis to therapeutic strategies: IL-21 as a novel potential therapeutic target. Current pharmaceutical biotechnology 21 22250707
2011 The role of IL-21 in hematological malignancies. Cytokine 21 21824785
2010 IL-21 is an immune activator that also mediates suppression via IL-10. Critical reviews in immunology 21 21175418
2007 Interleukin-21 (IL-21) controls inflammatory pathways in the gut. Endocrine, metabolic & immune disorders drug targets 20 18220949