Affinage

IL22

Interleukin-22 · UniProt Q9GZX6

Length
179 aa
Mass
20.0 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2000 Medium

    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

    PMID:11197690

    Open questions at the time
    • Did not identify the transcription factors binding the IL-9-responsive element
    • No protein-level functional characterization
  2. 2005 High

    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

    PMID:15983417

    Open questions at the time
    • No co-crystal structure with the receptor heterodimer
    • Functional consequence of the main-chain differences at binding sites not tested
  3. 2008 Medium

    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

    PMID:18684158 PMID:19016525

    Open questions at the time
    • JAK kinase mediating STAT3 activation not yet defined
    • Mechanism of receptor exclusion from immune cells unknown
  4. 2010 Medium

    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

    PMID:20870942

    Open questions at the time
    • Did not establish hepatic STAT3 dependence directly
    • Physiological versus pharmacological relevance of systemic doses unclear
  5. 2013 High

    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

    PMID:24130494 PMID:24796415

    Open questions at the time
    • 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
  6. 2014 High

    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

    PMID:24459235 PMID:25063867 PMID:27456484

    Open questions at the time
    • Determinants switching IL-22 between protective and toxic outcomes not defined
    • Cell-of-origin of IL-22 in each tissue not fully resolved
  7. 2015 High

    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

    PMID:25120745 PMID:26130064 PMID:26298743 PMID:26432894

    Open questions at the time
    • Whether Tyk2 is the dominant JAK in non-intestinal tissues not tested
    • AKT/ERK arm activation mechanisms in tumor cells incompletely defined
  8. 2016 High

    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

    PMID:27067005 PMID:27678220

    Open questions at the time
    • In vivo contribution of each IL-22BP isoform not separately measured
    • Structural basis of differential isoform potency unknown
  9. 2017 High

    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

    PMID:28842466 PMID:29980608

    Open questions at the time
    • Integration of NF-κB with STAT and AhR inputs on the promoter not mapped
    • Dexamethasone target genes beyond NF-κB modulation not defined
  10. 2018 High

    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

    PMID:29920352 PMID:30366940

    Open questions at the time
    • 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
  11. 2019 High

    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

    PMID:31344598 PMID:34755534

    Open questions at the time
    • Mechanism by which AhR represses SOCS3 not defined
    • STAT1 versus STAT3 contributions to antiviral ISGs not separated
  12. 2019 High

    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

    PMID:31028121

    Open questions at the time
    • Interplay between CNS-32 and proximal promoter elements not integrated
    • Human conservation of CNS-32 function not tested
  13. 2020 High

    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

    PMID:31964625 PMID:32332067

    Open questions at the time
    • Stoichiometry and assembly of the STAT3-STAT5 complex unknown
    • In vivo significance of Tc22 cells not established
  14. 2021 High

    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

    PMID:33648937 PMID:33753942 PMID:34408754

    Open questions at the time
    • Whether VDR and Nrf2 inputs operate in the same cells not addressed
    • Downstream signaling of IL-22 in erythroid precursors not detailed
  15. 2022 High

    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

    PMID:25793261 PMID:35169117 PMID:35383266

    Open questions at the time
    • How soluble versus membrane TNF differentially engage DCs mechanistically not fully resolved
    • Generality of the IL-18 axis outside the intestine untested
  16. 2023 High

    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

    PMID:38054920

    Open questions at the time
    • Molecular link between IL-22R signaling and DDR component induction not defined
    • Reconciliation with earlier protective kidney regeneration role not established
  17. 2024 High

    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

    PMID:38733584 PMID:39317186

    Open questions at the time
    • How IL-22-STAT3 inhibits WNT-β-catenin mechanistically not defined
    • Whether enterocyte-shrinking mechanism applies in human metabolic disease untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • What determines the switch between IL-22's protective/regenerative and pathological/pro-death outputs in the same epithelial tissue remains unresolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3
Partners
IL10R2IL22RA1IL22RA2

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 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. Genomic sequencing, chromosomal mapping, luciferase reporter assay Genes and immunity Medium 11197690
2005 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. X-ray crystallography (2.6 Å resolution), structural comparison Acta crystallographica. Section D, Biological crystallography High 15983417
2008 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. Immunohistochemistry, gene array analysis, organotypic skin model European journal of immunology Medium 19016525
2008 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. Gene array analysis of cytokine-treated keratinocytes, organotypic skin model, immunohistochemistry The British journal of dermatology Medium 18684158
2010 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. Adenoviral delivery of IL-22, systemic IL-22 protein administration, biochemical and hematological analyses in mice Journal of immunology (Baltimore, Md. : 1950) Medium 20870942
2013 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. T cell differentiation assays, STAT3 activation assays, chromatin/epigenetic analysis of il22 promoter, AhR reporter assay, ILC-deficient mouse colitis model Nature communications High 24796415
2013 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. IL-22-deficient mouse infection models (Nippostrongylus brasiliensis, Trichuris muris), ex vivo and in vitro goblet cell marker induction assays PLoS pathogens High 24130494
2014 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. IL-22 transgenic mice, liver-specific STAT3 knockout mice, Cyp2E1 knockout mice, adenovirus-mediated IL-22 delivery, hepatotoxicity assays Journal of immunology (Baltimore, Md. : 1950) High 25063867
2014 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. IL-22 deficient mice, cell depletion experiments, IL-22 reconstitution, TLR4 blockade, in vitro necrotic cell/oxidative stress assays Journal of the American Society of Nephrology : JASN High 24459235
2014 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. Il22-/- mice, hepatic-specific Il22ra1 knockout mice, rIL-22 administration, in vitro C3 expression assays, opsonic capacity assays Journal of immunology (Baltimore, Md. : 1950) High 27456484
2015 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. IL-22 stimulation of SGC-7901 cells, siRNA knockdown of IL-22R1, AKT inhibitor, migration/invasion assays, Western blot International journal of clinical and experimental pathology Medium 25120745
2015 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. IL-22-/-ApoE-/- double knockout mice, in vitro SMC treatment with IL-22, gene expression analysis, immunohistochemistry Atherosclerosis Medium 26298743
2015 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. Global and conditional (IEC-specific) Tyk2-/- mice, DSS colitis model, Citrobacter rodentium infection, primary IEC p-STAT3 stimulation assays, rIL-22-Fc rescue Journal of immunology (Baltimore, Md. : 1950) High 26432894
2015 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. Transient overexpression of IL10R2 in HT29 cells, IL-22 stimulation, Western blot for p-STAT3/AKT/ERK, proliferation assays Cancer immunology research Medium 26130064
2016 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. Isoform-specific inhibitory activity assays, secretion assays, myeloid cell activation with TLR2 ligands and retinoic acid, IL-22/IL-17 cooperative gene induction assays Science signaling High 27678220
2016 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. Neutrophil stimulation assays, mTOR inhibitor, RORγt and AhR expression analysis, neutrophil depletion in colitis model, IL-22 blockade Journal of immunology (Baltimore, Md. : 1950) Medium 27067005
2017 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. ChIP assay (p65 binding to IL22 promoter), luciferase reporter assay, NF-κB inhibitor, IL-18/IL-15 stimulation of human ILC3s, dexamethasone treatment Journal of immunology (Baltimore, Md. : 1950) High 28842466 29980608
2018 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. 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 Science immunology High 30366940
2018 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. IL-22-/- mice, epicutaneous sensitization OVA model, intranasal cytokine instillation, cytokine neutralization antibodies, TH22-polarized T cell adoptive transfer The Journal of allergy and clinical immunology High 29920352
2019 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. Intestinal cell-specific AhR KO mice and organoids, IL-22 stimulation, SOCS3 deletion, pSTAT3 measurement, AOM/DSS carcinogenesis model American journal of physiology. Gastrointestinal and liver physiology High 34755534
2019 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). 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 Cytokine Medium 31344598
2019 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. 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 of immunology (Baltimore, Md. : 1950) High 31028121
2020 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. STAT5a/STAT5b KO mice, colitis model, ChIP for STAT3-STAT5 complex binding to IL-22 promoter, human and mouse colonic LP ILC3 stimulation assays Science immunology High 32332067
2020 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. In vitro T cell polarization assays, AhR dependence assays, cytotoxicity assays, transcriptome analysis, tumor growth assays with polarized T cells Cancer immunology research Medium 31964625
2021 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. 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 Frontiers in immunology High 34408754
2021 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. 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 of immunology (Baltimore, Md. : 1950) High 33648937
2021 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. 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 Nature immunology High 33753942
2022 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. Intestinal organoid culture, AIEC infection model, IL-22-/- and IL-18-/- mice, p-STAT3 ChIP on Il-18 promoter, cytokine rescue experiments Nature communications High 35169117
2022 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. RT-PCR, Western blot, confocal microscopy for IL-22R expression, BrdU proliferation assay, ELISA cell death assay, phospho-protein analysis in GBM lines PloS one Medium 25793261
2022 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. 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 Mucosal immunology High 35383266
2023 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. 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 Kidney international High 38054920
2024 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. Recombinant IL-22 administration in diet-induced MASLD mice, IEC-specific vs. hepatocyte-specific signaling analysis, STAT3 activation, WNT-β-catenin pathway assays Cell metabolism High 39317186
2024 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. MATH1+ cell-specific Il22Ra1 conditional KO mice, DSS colitis model, adenoviral B3galt5 rescue, glycan analysis, organoid assays, human UC tissue analysis Cell reports High 38733584

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. The British journal of dermatology 708 18684158
2020 The role of IL-22 in intestinal health and disease. The Journal of experimental medicine 381 32997932
2013 IL-22, not simply a Th17 cytokine. Immunological reviews 371 23405899
2018 Lactobacillus accelerates ISCs regeneration to protect the integrity of intestinal mucosa through activation of STAT3 signaling pathway induced by LPLs secretion of IL-22. Cell death and differentiation 319 29459771
2018 Bacteria engineered to produce IL-22 in intestine induce expression of REG3G to reduce ethanol-induced liver disease in mice. Gut 300 30448775
2011 Recent advances in IL-22 biology. International immunology 265 21393631
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
2000 IL-TIF/IL-22: genomic organization and mapping of the human and mouse genes. Genes and immunity 175 11197690
2014 Directing traffic: IL-17 and IL-22 coordinate pulmonary immune defense. Immunological reviews 163 24942687
2018 Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab. The Journal of allergy and clinical immunology 151 30121291
2010 IL-22 induces an acute-phase response. Journal of immunology (Baltimore, Md. : 1950) 142 20870942
2014 IL-21 induces IL-22 production in CD4+ T cells. Nature communications 137 24796415
2013 The role of IL-22 and Th22 cells in human skin diseases. Journal of dermatological science 136 23746568
2018 Type 3 cytokines IL-17A and IL-22 drive TGF-β-dependent liver fibrosis. Science immunology 135 30366940
2009 IL-22: a critical mediator in mucosal host defense. Journal of molecular medicine (Berlin, Germany) 131 19219418
2013 IL-22 mediates goblet cell hyperplasia and worm expulsion in intestinal helminth infection. PLoS pathogens 123 24130494
2014 Toll-like receptor 4-induced IL-22 accelerates kidney regeneration. Journal of the American Society of Nephrology : JASN 122 24459235
2012 Healing of intestinal inflammation by IL-22. Inflammatory bowel diseases 109 22359410
2013 IL-22 and IDO1 affect immunity and tolerance to murine and human vaginal candidiasis. PLoS pathogens 99 23853597
2010 Distinct roles of IL-22 in human psoriasis and inflammatory bowel disease. Cytokine & growth factor reviews 96 21106435
2016 Epithelial IL-23R Signaling Licenses Protective IL-22 Responses in Intestinal Inflammation. Cell reports 93 27524624
2008 IL-22 and inflammation: leukin' through a glass onion. European journal of immunology 92 19016525
2016 mTOR Mediates IL-23 Induction of Neutrophil IL-17 and IL-22 Production. Journal of immunology (Baltimore, Md. : 1950) 90 27067005
2022 IL-22 initiates an IL-18-dependent epithelial response circuit to enforce intestinal host defence. Nature communications 89 35169117
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
2017 IL-18 Drives ILC3 Proliferation and Promotes IL-22 Production via NF-κB. Journal of immunology (Baltimore, Md. : 1950) 84 28842466
2014 IL-22, cell regeneration and autoimmunity. Cytokine 74 25467639
2018 IL22 Inhibits Epithelial Stem Cell Expansion in an Ileal Organoid Model. Cellular and molecular gastroenterology and hepatology 72 30364840
2019 IL-22 and its receptors are increased in human and experimental COPD and contribute to pathogenesis. The European respiratory journal 71 31196943
2013 IL-22 in tissue-protective therapy. British journal of pharmacology 68 23530726
2013 A tale of two cytokines: IL-17 and IL-22 in asthma and infection. Expert review of respiratory medicine 68 24325586
2019 IL-17 and IL-22 Promote Keratinocyte Stemness in the Germinative Compartment in Psoriasis. The Journal of investigative dermatology 63 30684548
2021 IL-22 Binding Protein (IL-22BP) in the Regulation of IL-22 Biology. Frontiers in immunology 62 34868019
2017 Limited Presence of IL-22 Binding Protein, a Natural IL-22 Inhibitor, Strengthens Psoriatic Skin Inflammation. Journal of immunology (Baltimore, Md. : 1950) 60 28356382
2013 IL-22 modulates IL-17A production and controls inflammation and tissue damage in experimental dengue infection. European journal of immunology 54 23505056
2020 IL-23 and IL-2 activation of STAT5 is required for optimal IL-22 production in ILC3s during colitis. Science immunology 53 32332067
2014 Acute and chronic effects of IL-22 on acetaminophen-induced liver injury. Journal of immunology (Baltimore, Md. : 1950) 53 25063867
2023 IL-22 alters gut microbiota composition and function to increase aryl hydrocarbon receptor activity in mice and humans. Microbiome 52 36894983
2022 Role of IL-22 in homeostasis and diseases of the skin. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 52 35316548
2011 Research in practice: IL-22 and IL-20: significance for epithelial homeostasis and psoriasis pathogenesis. Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG 52 21251229
2015 Pathogen Resistance Mediated by IL-22 Signaling at the Epithelial-Microbiota Interface. Journal of molecular biology 50 26497621
2017 Paeoniflorin suppressed IL-22 via p38 MAPK pathway and exerts anti-psoriatic effect. Life sciences 46 28456711
2016 Critical Role of IL-22/IL22-RA1 Signaling in Pneumococcal Pneumonia. Journal of immunology (Baltimore, Md. : 1950) 46 27456484
2015 IL-22 affects smooth muscle cell phenotype and plaque formation in apolipoprotein E knockout mice. Atherosclerosis 44 26298743
2014 Cytokines (interleukin-9, IL-17, IL-22, IL-25 and IL-33) and asthma. Advanced biomedical research 44 24949298
2015 Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis. Journal of immunology (Baltimore, Md. : 1950) 43 26432894
2024 Live Akkermansia muciniphila boosts dendritic cell retinoic acid synthesis to modulate IL-22 activity and mitigate colitis in mice. Microbiome 42 39734222
2018 IL-22 promotes allergic airway inflammation in epicutaneously sensitized mice. The Journal of allergy and clinical immunology 42 29920352
2015 CCL20 and IL22 Messenger RNA Expression After Adalimumab vs Methotrexate Treatment of Psoriasis: A Randomized Clinical Trial. JAMA dermatology 42 25946554
2005 Structure of insect-cell-derived IL-22. Acta crystallographica. Section D, Biological crystallography 42 15983417
2018 IL-22: An Underestimated Player in Natural Resistance to Tuberculosis? Frontiers in immunology 40 30319650
2017 Different Modulatory Effects of IL-17, IL-22, and IL-23 on Osteoblast Differentiation. Mediators of inflammation 40 28831209
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
2024 IL-22 resolves MASLD via enterocyte STAT3 restoration of diet-perturbed intestinal homeostasis. Cell metabolism 37 39317186
2021 Therapeutic Opportunities of IL-22 in Non-Alcoholic Fatty Liver Disease: From Molecular Mechanisms to Clinical Applications. Biomedicines 37 34944732
2014 IL-22 promotes the migration and invasion of gastric cancer cells via IL-22R1/AKT/MMP-9 signaling. International journal of clinical and experimental pathology 37 25120745
2020 Elevated IL-22 in psoriasis plays an anti-apoptotic role in keratinocytes through mediating Bcl-xL/Bax. Apoptosis : an international journal on programmed cell death 35 32632545
2018 The role of IL-22 in the resolution of sterile and nonsterile inflammation. Clinical & translational immunology 32 29713472
2014 Role of IL-17 and IL-22 in autoimmunity and cancer. Actas dermo-sifiliograficas 31 25398491
2022 TNF hampers intestinal tissue repair in colitis by restricting IL-22 bioavailability. Mucosal immunology 28 35383266
2021 The good and the bad about separation anxiety: roles of IL-22 and IL-22BP in liver pathologies. Seminars in immunopathology 28 33851257
2022 The Roles of IL-22 and Its Receptor in the Regulation of Inflammatory Responses in the Brain. International journal of molecular sciences 27 35054942
2020 Characterization of IL-22 Bioactivity and IL-22-Positive Cells in Grass Carp Ctenopharyngodon idella. Frontiers in immunology 27 33178219
2023 IL-22 as a target for therapeutic intervention: Current knowledge on its role in various diseases. Cytokine 26 37441942
2015 IL22/IL-22R pathway induces cell survival in human glioblastoma cells. PloS one 26 25793261
2023 IL-22 is secreted by proximal tubule cells and regulates DNA damage response and cell death in acute kidney injury. Kidney international 25 38054920
2023 Current Knowledge of Th22 Cell and IL-22 Functions in Infectious Diseases. Pathogens (Basel, Switzerland) 24 36839448
2016 Human IL-22 binding protein isoforms act as a rheostat for IL-22 signaling. Science signaling 24 27678220
2020 IL-22 promotes tumor growth of breast cancer cells in mice. Aging 23 32649314
2020 IL-22 Paucity in APECED Is Associated With Mucosal and Microbial Alterations in Oral Cavity. Frontiers in immunology 22 32477345
2018 IL-22 sustains epithelial integrity in progressive kidney remodeling and fibrosis. Physiological reports 22 30156011
2015 IL-22: a promising candidate to inhibit viral-induced liver disease progression and hepatocellular carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 22 26541758
2023 Modulation of tryptophan metabolism via AHR-IL22 pathway mediates the alleviation of DSS-induced colitis by chitooligosaccharides with different degrees of polymerization. Carbohydrate polymers 21 37567716
2021 Loss of aryl hydrocarbon receptor suppresses the response of colonic epithelial cells to IL22 signaling by upregulating SOCS3. American journal of physiology. Gastrointestinal and liver physiology 20 34755534
2020 Effects of IL-22 on cardiovascular diseases. International immunopharmacology 20 32062077
2019 Induction of IL-22 protein and IL-22-producing cells in rainbow trout Oncorhynchus mykiss. Developmental and comparative immunology 20 31306696
2019 Interleukin-22 (IL-22) Binding Protein Constrains IL-22 Activity, Host Defense, and Oxidative Phosphorylation Genes during Pneumococcal Pneumonia. Infection and immunity 20 31451621
2018 IL-17 and IL-22 production in HIV+ individuals with latent and active tuberculosis. BMC infectious diseases 20 29996789
2016 IL-22 dampens the T cell response in experimental malaria. Scientific reports 20 27311945
2015 Differential Requirements for IL-17A and IL-22 in Cecal versus Colonic Inflammation Induced by Helicobacter hepaticus. The American journal of pathology 20 26458765
2024 AhR ligands from LGG metabolites promote piglet intestinal ILC3 activation and IL-22 secretion to inhibit PEDV infection. Journal of virology 19 39012142
2023 Dihydromyricetin Protects Intestinal Barrier Integrity by Promoting IL-22 Expression in ILC3s through the AMPK/SIRT3/STAT3 Signaling Pathway. Nutrients 19 36678226
2019 Runx1 and RORγt Cooperate to Upregulate IL-22 Expression in Th Cells through Its Distal Enhancer. Journal of immunology (Baltimore, Md. : 1950) 19 31028121
2018 IL-17 and IL-22 elicited by a DNA vaccine encoding ROP13 associated with protection against Toxoplasma gondii in BALB/c mice. Journal of cellular physiology 19 30565688
2017 Modified apple polysaccharide prevents colitis through modulating IL-22 and IL-22BP expression. International journal of biological macromolecules 19 28579463
2014 Treg cells: a potential regulator for IL-22 expression? International journal of clinical and experimental pathology 19 24551268
2021 Blockade of IL-22 signaling reverses erythroid dysfunction in stress-induced anemias. Nature immunology 18 33753942
2021 Nrf2 through Aryl Hydrocarbon Receptor Regulates IL-22 Response in CD4+ T Cells. Journal of immunology (Baltimore, Md. : 1950) 17 33648937
2019 IL-22 Binding Protein Promotes the Disease Process in Multiple Sclerosis. Journal of immunology (Baltimore, Md. : 1950) 17 31292217
2018 Glucocorticoids Inhibit Group 3 Innate Lymphocyte IL-22 Production. Journal of immunology (Baltimore, Md. : 1950) 17 29980608
2024 IL-22 signaling promotes sorafenib resistance in hepatocellular carcinoma via STAT3/CD155 signaling axis. Frontiers in immunology 16 38596684
2024 IL-22 promotes mucin-type O-glycosylation and MATH1+ cell-mediated amelioration of intestinal inflammation. Cell reports 16 38733584
2021 Vitamin D Inhibits IL-22 Production Through a Repressive Vitamin D Response Element in the il22 Promoter. Frontiers in immunology 16 34408754
2019 Blockade of IL-33R/ST2 Signaling Attenuates Toxoplasma gondii Ileitis Depending on IL-22 Expression. Frontiers in immunology 16 31057534
2019 IL-22 suppresses HSV-2 replication in human cervical epithelial cells. Cytokine 16 31344598
2024 Bacterial Sphingolipids Exacerbate Colitis by Inhibiting ILC3-derived IL-22 Production. Cellular and molecular gastroenterology and hepatology 15 38704148
2024 OLFM4 modulates intestinal inflammation by promoting IL-22+ILC3 in the gut. Communications biology 15 39075283
2021 IL-22 Signaling in the Tumor Microenvironment. Advances in experimental medicine and biology 15 33559856

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