Affinage

IL17A

Interleukin-17A · UniProt Q16552

Round 2 corrected
Length
155 aa
Mass
17.5 kDa
Annotated
2026-04-28
130 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL-17A is a disulfide-linked homodimeric cytokine with a cystine-knot fold, secreted by Th17 cells, γδ T cells, mast cells, and neutrophils, that orchestrates innate and adaptive immune responses at mucosal and barrier surfaces (PMID:8390535, PMID:8676080, PMID:21606249, PMID:21982596). It signals through an IL-17RA/IL-17RC heterodimer assembled in a 'tip-to-tip' architecture, recruiting the adaptor Act1 via SEFIR–SEFIR domain interaction, which engages TRAF6 to activate NF-κB, MAPK, and C/EBP pathways, inducing IL-6, IL-8, G-CSF, CXC chemokines, and antimicrobial peptides in epithelial and stromal target cells (PMID:35863378, PMID:18061473, PMID:9973514, PMID:16982811). Beyond canonical immunity, IL-17A drives osteoclastogenesis through osteoblast RANKL/PGE2 upregulation, inhibits adipogenesis and glucose uptake, promotes metabolic reprogramming of lymph node fibroblastic reticular cells via IκBζ/CPT1A induction, and acts directly on cortical neurons through IL-17Ra to modulate social behavior (PMID:10225978, PMID:21037091, PMID:30962593, PMID:31853066). Autosomal recessive IL-17RA deficiency in humans causes chronic mucocutaneous candidiasis, establishing a non-redundant role for IL-17A signaling in antifungal host defense (PMID:21350122).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1993 High

    Identification of IL-17A (CTLA-8) as a novel T-cell-derived cytokine with viral homology resolved the question of whether the HVS ORF13-like gene had a mammalian counterpart and established a new cytokine family.

    Evidence cDNA subtraction cloning from activated murine T cell hybridoma; sequence analysis revealing 57% identity with HVS ORF13

    PMID:8390535

    Open questions at the time
    • Protein structure unknown
    • Receptor unidentified
    • Biological function of the secreted protein not yet determined
  2. 1996 High

    Demonstration that recombinant IL-17A is a glycosylated homodimer that stimulates stromal cells to produce IL-6, IL-8, G-CSF, and PGE2—but does not act directly on hematopoietic cells—defined its cellular target specificity and established it as an indirect regulator of granulopoiesis and inflammation.

    Evidence Recombinant protein expression; cytokine ELISA on fibroblasts, epithelial and endothelial cells; CD34+ progenitor co-culture differentiation assays

    PMID:7499828 PMID:8676080

    Open questions at the time
    • Receptor identity unknown
    • Signaling pathway not mapped
    • In vivo relevance not yet tested
  3. 1999 High

    Two key effector functions were mechanistically delineated: IL-17A induces osteoclastogenesis indirectly via osteoblast COX-2/PGE2 and RANKL upregulation, and recruits neutrophils to airways by inducing CXC chemokines from bronchial epithelium, establishing it as a master coordinator of tissue-level innate defense and bone remodeling.

    Evidence Osteoblast–osteoclast progenitor coculture with pharmacological inhibitors (indomethacin, NS398, OCIF); in vivo intratracheal IL-17A instillation with anti-MIP-2/anti-IL-8 neutralization and BAL analysis

    PMID:10225978 PMID:9973514

    Open questions at the time
    • Receptor subunit composition still undefined
    • Intracellular signaling cascade not yet identified
    • Source T cell subset not characterized
  4. 2002 High

    Discovery that IL-23 (not IL-12) specifically drives IL-17A production from memory T cells resolved the upstream regulatory signal and foreshadowed the Th17 lineage as a distinct effector program.

    Evidence Cytokine stimulation of murine memory T cells; IL-17A ELISA comparing IL-23 versus IL-12

    PMID:12417590

    Open questions at the time
    • Th17 lineage not yet formally defined
    • Transcription factors controlling IL-17A expression unknown
    • Role of TGF-β not yet established
  5. 2006 High

    Identification of IL-17A co-expression with IL-17F and IL-22 in Th17 cells, and demonstration of IL-17A/IL-22 synergy in inducing antimicrobial peptides in keratinocytes, established the cooperative cytokine module operating at epithelial barriers.

    Evidence Th17 differentiation assays; intracellular cytokine staining; keratinocyte stimulation with recombinant cytokines; RT-PCR for β-defensin 2, S100A7/A8/A9

    PMID:16982811

    Open questions at the time
    • Receptor complex composition not yet resolved
    • Relative contribution of IL-17A versus IL-17F in vivo unclear
  6. 2007 High

    Genetic evidence that Act1 is the obligate proximal adaptor for IL-17R signaling—recruited through a SEFIR–SEFIR domain interaction—resolved the long-standing question of how IL-17A activates NF-κB and MAPK without using JAK-STAT or classical TIR domains.

    Evidence Act1 knockout mice resistant to EAE and colitis; domain deletion mapping; co-immunoprecipitation with IL-17R

    PMID:18061473 PMID:19575028

    Open questions at the time
    • TRAF specificity downstream of Act1 not fully dissected
    • Role of IL-17RC as obligate co-receptor not yet structurally proven
  7. 2009 High

    The crystal structure of IL-17A at 2.6 Å confirmed a cystine-knot homodimer fold and revealed that a neutralizing antibody epitope spans both monomers, defining the quaternary receptor-binding surface as a druggable target.

    Evidence X-ray crystallography of IL-17A–Fab complex; H/D exchange mass spectrometry; site-directed mutagenesis; cell-based neutralization

    PMID:19835883

    Open questions at the time
    • Full receptor complex structure not yet determined
    • IL-17A/F heterodimer structure unresolved
  8. 2011 High

    Three paradigm-shifting discoveries redefined IL-17A biology: mast cells and neutrophils (not only T cells) are major IL-17A sources in psoriatic skin; dermal γδ T cells are the principal IL-17A producers driving IL-23-dependent skin inflammation; and human IL-17RA deficiency causes chronic mucocutaneous candidiasis, establishing non-redundant antifungal host defense.

    Evidence Immunohistochemistry of human psoriatic biopsies; Tcrd−/−, Tcra−/−, Il17ra−/− mice with IL-23 and imiquimod models; human genetic sequencing with functional receptor-ligand assays

    PMID:21350122 PMID:21606249 PMID:21982596

    Open questions at the time
    • Relative contribution of each cellular source across tissues not quantified
    • Whether IL-17A and IL-17F are functionally redundant in antifungal defense remains unclear
  9. 2013 High

    Identification of STAT1 as a required downstream mediator of IL-17A-enhanced islet chemokine expression and apoptosis extended the signaling repertoire beyond NF-κB/MAPK and showed IL-17A acts as a cytokine amplifier in inflammatory tissue damage.

    Evidence STAT1 RNAi in primary human islets; Stat1 knockout mouse islets; cytokine co-stimulation; ELISA and viability assays

    PMID:24352375

    Open questions at the time
    • Whether STAT1 activation is direct or requires Act1/TRAF machinery is unclear
    • Generalizability beyond pancreatic islets not established
  10. 2016 High

    Structural druggability of IL-17A was directly demonstrated by macrocyclic peptides that bind its receptor-interaction surface and block IL-17RA engagement, validating protein–protein interface targeting for this cytokine.

    Evidence NMR and X-ray crystallography of peptide–IL-17A complexes; SPR binding; cell-based neutralization

    PMID:27527709

    Open questions at the time
    • In vivo pharmacokinetics and efficacy of macrocyclic antagonists not demonstrated
    • Selectivity over IL-17A/F heterodimer not addressed
  11. 2019 High

    IL-17A was shown to act directly on cortical neurons (S1DZ) via IL-17Ra to promote sociability, and separately to drive metabolic reprogramming of lymph node FRCs via IκBζ-dependent CPT1A induction—revealing non-immune physiological roles that fundamentally broadened the functional scope of this cytokine.

    Evidence Stereotactic IL-17A injection into S1DZ rescuing social deficits in MIA/Cntnap2/Fmr1/Shank3 mutant mice; neuron-specific Il17ra conditional KO; FRC-specific IL-17R conditional KO with metabolic profiling in EAE/colitis models

    PMID:30962593 PMID:31853066

    Open questions at the time
    • Neuronal signaling intermediates downstream of IL-17Ra in cortex not identified
    • Whether FRC metabolic reprogramming is conserved across all secondary lymphoid organs is unknown
  12. 2022 High

    Cryo-EM structures of IL-17A–IL-17RA binary and IL-17A–IL-17RA–IL-17RC ternary complexes resolved the 'tip-to-tip' receptor assembly mechanism and revealed how IL-17RA functions dually as a direct cytokine binder and an allosterically recruited co-receptor.

    Evidence Cryo-EM; single-molecule imaging; structure–function mutagenesis; cell-based signaling assays

    PMID:35863378

    Open questions at the time
    • How tip-to-tip geometry drives Act1 recruitment at the cytoplasmic face is structurally unresolved
    • Structures of IL-17A/F heterodimer–receptor complexes not yet determined
  13. 2023 High

    Epigenetic and transcriptional control of IL-17A expression was elucidated: SIRT6 deacetylates RORγt at K192 to promote its binding to the IL-17A promoter, while STAT5/IL-2 signaling differentially regulates IL-17A versus IL-17F at a shared locus marked by a broad H3K4me3 domain; additionally, FXYD3 was identified as a positive-feedback amplifier of IL-17A signaling in keratinocytes by sequestering the negative regulator TRAF3 away from IL-17RA.

    Evidence Conditional Sirt6 KO mice; RORγt Co-IP and ChIP at IL-17A promoter; K192 deacetylation assays; scRNA-seq and ChIP-seq at IL17A-F locus; FXYD3 conditional keratinocyte KO in imiquimod model; competitive TRAF3 binding assays

    PMID:36693922 PMID:37244461 PMID:38135684

    Open questions at the time
    • Whether SIRT6-RORγt axis operates in non-epithelial IL-17A-producing cells is unknown
    • Complete enhancer architecture of the IL17A-F locus remains to be mapped
    • Whether FXYD3-TRAF3 axis operates beyond skin keratinocytes is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: (1) full structural resolution of the cytoplasmic signaling complex (Act1–TRAF6 assembly on the receptor), (2) whether IL-17A/F heterodimer and IL-17A homodimer signal through identical or distinct receptor geometries, (3) the neuronal signaling cascade downstream of IL-17Ra in the CNS, and (4) cell-type-specific transcriptional versus post-transcriptional regulation of IL-17A output across innate and adaptive sources.
  • Cytoplasmic signaling complex structure unresolved
  • IL-17A/F heterodimer receptor complex not structurally characterized
  • Neuronal downstream signaling unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 6 GO:0060089 molecular transducer activity 2
Localization
GO:0005576 extracellular region 4
Pathway
R-HSA-168256 Immune System 12 R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 5 R-HSA-112316 Neuronal System 1 R-HSA-1500931 Cell-Cell communication 1
Partners
FXYD3IL17RAIL17RCIL22TRAF3TRAF6TRAF6IP2
Complex memberships
IL-17A homodimerIL-17A–IL-17RA–IL-17RC ternary signaling complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 IL-17A (then named CTLA-8) was cloned from an activated murine T cell hybridoma; its cDNA encodes a 150-amino-acid secreted protein with 57% homology to Herpesvirus saimiri ORF13, and the mRNA contains AU-rich instability elements characteristic of cytokines. The human gene was mapped to chromosome 2q31. cDNA library subtraction, differential screening, sequence analysis, radioactive in situ hybridization Journal of immunology High 8390535
1995 Human IL-17A cDNA was cloned from a CD4+ T cell library; the protein is predicted to be 155 amino acids with an N-terminal signal peptide and 72% identity to Herpesvirus saimiri HVS13. Recombinant hIL-17A (expressed in CV1/EBNA cells) was secreted in glycosylated and non-glycosylated forms and induced IL-6, IL-8 production, and enhanced ICAM-1 surface expression on human fibroblasts. cDNA cloning, recombinant protein expression in CV1/EBNA cells, cytokine ELISA, FACS Journal of immunology High 7499828
1996 Human IL-17A (hIL-17) is a glycoprotein of 155 amino acids secreted as a homodimer by activated memory CD4+ T cells. hIL-17A, though devoid of direct effects on hematopoietic cells, stimulates epithelial, endothelial, and fibroblastic stromal cells to secrete IL-6, IL-8, G-CSF, and prostaglandin E2, and enables fibroblasts to support proliferation and preferential neutrophil maturation of CD34+ hematopoietic progenitors. Recombinant protein expression, co-culture assays, cytokine ELISA, CD34+ progenitor differentiation assay The Journal of experimental medicine High 8676080
1999 IL-17A stimulates osteoblasts (not osteoclast progenitors directly) to upregulate COX-2-dependent prostaglandin E2 synthesis and osteoclast differentiation factor (ODF/RANKL) mRNA expression, which in turn drives osteoclast progenitor differentiation into mature osteoclasts; direct osteoblast-osteoclast progenitor contact was required. Indomethacin or the COX-2 inhibitor NS398 completely blocked IL-17A-induced osteoclastogenesis, and OCIF (decoy receptor for ODF) completely inhibited differentiation. Coculture of mouse hematopoietic cells and primary osteoblasts with recombinant human IL-17A; pharmacological inhibition (indomethacin, NS398); ODF neutralization (OCIF); TRAP staining, calcitonin receptor expression, dentine pit formation assay; RT-PCR; PGE2 ELISA The Journal of clinical investigation High 10225978
1999 IL-17A recruits neutrophils into the airways by inducing release of C-X-C chemokines (IL-8/hIL-8; rat MIP-2) from bronchial epithelial cells; conditioned medium from IL-17A-treated bronchial epithelial cells enhanced neutrophil migration in vitro, an effect blocked by anti-IL-8 antibody. In vivo intratracheal IL-17A instillation selectively recruited neutrophils, reduced by anti-MIP-2 antibody. TNF-α potentiated, and glucocorticoids inhibited, IL-17A-induced CXC chemokine release. In vitro IL-8 ELISA and mRNA expression in bronchial epithelial/endothelial cells; neutrophil chemotaxis assay; in vivo intratracheal instillation in rats; BAL differential cell counts; neutralizing antibodies; glucocorticoid co-treatment Journal of immunology High 9973514
2002 IL-23 drives production of IL-17A (and IL-17F) from memory T cells; IL-23, produced by activated dendritic cells, promotes a distinct CD4+ T cell activation state characterized by IL-17 secretion, distinguishable from IL-12-driven Th1 responses (IL-12 had only marginal effects on IL-17 production). Cytokine stimulation of murine memory T cells; ELISA for IL-17 and IL-17F; comparison of IL-23 vs IL-12 effects The Journal of biological chemistry High 12417590
2006 Th17 cells co-express IL-17A, IL-17F, and IL-22; IL-22 expression, like IL-17A, is initiated by TGF-β in the context of IL-6 and other proinflammatory cytokines, with subsequent expansion dependent on IL-23. IL-22 synergizes with IL-17A or IL-17F to induce antimicrobial peptides (β-defensin 2, S100A9, S100A7, S100A8) in primary keratinocytes. Th17 cell differentiation assays; intracellular cytokine staining; keratinocyte stimulation with recombinant cytokines; RT-PCR for antimicrobial peptides The Journal of experimental medicine High 16982811
2007 Act1 (also known as CIKS) functions as a key positive signaling adaptor for IL-17A receptor (IL-17R) signaling; Act1-deficient mice are resistant to TH17-dependent EAE and colitis. Act1 interacts with IL-17R through its C-terminal SEFIR domain, whereas its interaction with CD40/BAFFR is mediated through a different TRAF-binding site, demonstrating domain-separated dual functions. Act1 knockout mice; domain deletion/mapping analysis; IL-17R co-immunoprecipitation; EAE and colitis models Cytokine High 18061473
2009 The crystal structure of IL-17A in complex with a neutralizing human Fab (CAT-2200) was solved at 2.6 Å resolution. IL-17A forms a disulfide-linked homodimer adopting a cystine-knot fold similar to IL-17F. The epitope involves 12 residues from the quaternary structure of the dimer, with each Fab contacting both monomers; 16 residues in the Fab paratope (all CDRs contributing) mediate binding. The receptor-binding cavity predicted for IL-17 family members is structurally consistent with the observed interaction. X-ray crystallography at 2.6 Å; H/D exchange mass spectrometry; site-directed mutagenesis; cell-based neutralization assay Journal of molecular biology High 19835883
2009 IL-17A signals through the IL-17RA receptor, which contains unique functional motifs (SEFIR domain) distinct from other cytokine receptor families. The proximal signaling mediator Act1 is recruited via SEFIR-SEFIR domain interaction and is required for downstream NF-κB, MAPK, and C/EBP pathway activation. Domain functional analysis, genetic knockouts, signaling pathway assays (NF-κB, MAPK reporters) Nature reviews. Immunology High 19575028
2010 IL-17A inhibits adipogenesis and moderates adipose tissue accumulation in vivo; IL-17A-deficient mice show enhanced diet-induced obesity and accelerated adipose tissue accumulation. IL-17A suppresses adipocyte differentiation from 3T3-L1 preadipocytes in vitro, inhibiting expression of proadipogenic transcription factors, adipokines, and genes involved in lipid and glucose metabolism. On differentiated adipocytes, IL-17A impairs glucose uptake. IL-17A knockout mice on high-fat and low-fat diets; in vitro 3T3-L1 differentiation assay; RT-PCR for adipogenic genes; glucose uptake assay; glucose tolerance and insulin sensitivity tests Journal of immunology High 21037091
2011 Mast cells and neutrophils, not T cells, are the predominant cellular sources of IL-17A protein in human psoriatic skin. These innate immune cells release IL-17A through extracellular trap (ET) formation; IL-23 and IL-1β can induce mast cell ET formation and degranulation. Immunohistochemistry and immunofluorescence of psoriatic skin biopsies; cell density quantification; stimulation of primary mast cells with IL-23 and IL-1β; ET visualization Journal of immunology High 21606249
2011 IL-23 primarily stimulates dermal γδ T cells (not CD4+ Th17 cells) to produce IL-17A, driving skin inflammation. Dermal γδ T cells constitutively express IL-23R and RORγt. Epidermal hyperplasia and inflammation induced by IL-23 were significantly reduced in Tcrd−/− and Il17ra−/− mice but occurred normally in Tcra−/− mice, establishing γδ T cells as the major IL-17A producers in skin. Genetic knockout mice (Tcrd−/−, Tcra−/−, Il17ra−/−); IL-23 intradermal injection model; imiquimod-induced skin pathology model; flow cytometry; immunohistochemistry of human psoriatic skin Immunity High 21982596
2011 Inborn errors of IL-17A immunity establish its essential role in mucocutaneous anti-Candida defense in humans: autosomal recessive IL-17RA deficiency completely abolishes cellular responses to IL-17A and IL-17F homo- and heterodimers, while autosomal dominant IL-17F deficiency partially impairs, but does not abolish, IL-17A/F heterodimer activity. Genetic sequencing; receptor-ligand binding assays; functional cell stimulation assays with homo- and heterodimers; patient phenotypic characterization Science High 21350122
2016 IL-17A exacerbates diabetic retinopathy by promoting Müller cell functional impairment via the Act1/TRAF6/IKK/NF-κB signaling pathway. Act1 knockdown or IKK inhibition blocked IL-17A-enhanced downstream signaling activation. IL-17A intravitreal injection aggravated retinal vascular leukostasis, vascular leakage, and ganglion cell apoptosis, while Act1 silencing or anti-IL-17A mAb ameliorated these effects. In vitro high-glucose Müller cell (rMC-1) stimulation; Act1 siRNA knockdown; IKK inhibitor; in vivo Akita diabetic mouse model with intravitreal IL-17A injection; Western blot for pathway components; GFAP/VEGF/glutamate assays; FACS for apoptosis; retinal angiography Experimental & molecular medicine High 27980343
2019 IL-17A directly affects neuronal activity in the primary somatosensory cortex dysgranular zone (S1DZ) to promote sociability in neurodevelopmental disorder models. Direct injection of IL-17A into S1DZ was sufficient to rescue social behavior deficits in both MIA offspring and monogenic mutant mice (Cntnap2, Fmr1, Shank3). Conditional deletion of IL-17Ra in S1DZ neurons eliminated the ability of LPS (which induces IL-17A) to reverse sociability phenotypes in MIA offspring. MIA mouse model; direct stereotactic IL-17A injection into S1DZ; conditional neuron-specific IL-17Ra knockout; social behavior assays; in vivo cytokine measurement; electrophysiology Nature High 31853066
2019 IL-17A is required for proliferation and metabolic reprogramming of lymph node fibroblastic reticular cells (FRCs) during inflammation. Without IL-17R signaling, activated FRCs undergo cell cycle arrest and apoptosis with nutrient stress. IL-17 signaling in FRCs induces the transcriptional co-activator IκBζ, which mediates increased glucose uptake and expression of Cpt1a (encoding CPT1A, a rate-limiting enzyme of mitochondrial fatty acid oxidation). EAE and colitis models; FRC-specific IL-17R conditional knockout; cell cycle analysis; apoptosis assays; metabolic profiling; IκBζ induction assays; Cpt1a expression by RT-PCR; germinal center and antibody production assays Nature immunology High 30962593
2022 Cryo-EM structures of IL-17A–IL-17RA binary and IL-17A–IL-17RA–IL-17RC ternary complexes revealed that IL-17A interacts directly with both IL-17RA and IL-17RC. A 'tip-to-tip' receptor–receptor geometry is the key organizing principle of IL-17 receptor family signaling assemblies. IL-17RA acts dually: directly engaging IL-17A cytokine or alternatively functioning as a co-receptor allosterically promoted by the cytokine–primary receptor interaction. Cryo-electron microscopy; single-molecule imaging; cell-based signaling assays; structure-function mutagenesis Nature High 35863378
2016 Macrocyclic peptide antagonists bind directly to IL-17A protein, competitively blocking the IL-17A–IL-17RA interaction. Characterization of linear peptide binding sites on IL-17A enabled structure-guided design of macrocyclic IL-17A antagonists, demonstrating that the receptor-binding surface of IL-17A is a druggable site for small/medium molecules. NMR and X-ray crystallography of peptide–IL-17A complexes; SPR binding assays; cell-based IL-17A neutralization assay; structure-guided medicinal chemistry Scientific reports High 27527709
2019 TRAF proteins (TRAF2, TRAF3, TRAF5, TRAF6) mediate IL-17A receptor downstream signaling; TRAF6 is recruited to the Act1 adaptor to activate NF-κB and MAPK pathways following IL-17RA engagement, while TRAF2 and TRAF5 promote mRNA stabilization of target transcripts. Different TRAFs therefore mediate distinct branches of IL-17A signaling. Co-immunoprecipitation; genetic knockouts; reporter assays for NF-κB and MAPK; mRNA stability assays Frontiers in immunology Medium 31316496
2013 IL-17A augments IL-1β+IFN-γ- and TNF-α+IFN-γ-induced proinflammatory chemokine (CXCL9, CXCL10) mRNA and protein expression and apoptosis in human pancreatic islets. STAT1 knockdown in human islets prevented cytokine- or IL-17A+cytokine-induced apoptosis and expression of these chemokines, and similar results were obtained in islets from Stat1 knockout mice, establishing STAT1 as a required downstream mediator of IL-17A-induced islet damage. Primary human islet stimulation; RNA interference (STAT1 knockdown); STAT1 knockout mouse islets; RT-PCR; ELISA; nuclear dye viability assay Diabetologia High 24352375
2014 IL-17A activates ERK1/2 within 15 minutes in oligodendrocyte progenitor cells (OPCs), promoting OPC exit from the cell cycle and differentiation into mature myelin-forming cells with increased proteolipid protein expression, and inducing chemokine expression at 2 days. Primary murine OPC cultures; IL-17A stimulation; Western blot for phospho-ERK1/2; cell cycle analysis (BrdU, Ki67); viability assay; cerebellar slice remyelination assay; RT-PCR for PLP and chemokines Glia Medium 25557204
2018 IL-17A induces epithelial-mesenchymal transition (EMT) in intestinal epithelial cells (IEC-6), characterized by reduced E-cadherin and increased vimentin, Snail, and α-SMA expression, contributing to intestinal fibrosis. Anti-IL-17A treatment in a TNBS-induced mouse colitis/fibrosis model reduced EMT markers in mouse intestine. IEC-6 cell stimulation with IL-17A at increasing concentrations; RT-PCR and Western blot for EMT markers; anti-IL-17A antibody treatment in TNBS mouse model; histology Digestive diseases and sciences Medium 30097894
2023 SIRT6 directly interacts with RORγt and mediates RORγt deacetylation at lysine 192 via PPXY motifs; this promotes RORγt recruitment to the IL-17A gene promoter and enhances IL-17A transcription. Airway epithelial cell-specific deletion of Sirt6 in mice protects against allergen-induced airway inflammation and remodeling by inhibiting IL-17A-mediated inflammatory chemokines and mesenchymal reprogramming. Conditional Sirt6 knockout mice; co-immunoprecipitation of SIRT6 and RORγt; chromatin immunoprecipitation for RORγt at IL-17A promoter; deacetylation assays at K192; allergen-induced asthma model; cytokine assays Nature communications High 38135684
2023 FXYD3 promotes IL-17A signaling in keratinocytes by competitively binding TRAF3, thereby preventing TRAF3 from interacting with IL-17RA. This competition removes a negative constraint on the IL-17RA–ACT1 complex formation, enhancing NF-κB and MAPK activation and proinflammatory factor expression. IL-17A itself induces FXYD3 expression, creating a positive feedback loop. FXYD3 deletion in keratinocytes attenuates psoriasis-like phenotype in an IMQ mouse model. Co-immunoprecipitation; competitive binding assays; FXYD3 conditional keratinocyte knockout; IMQ-induced psoriasis mouse model; NF-κB and MAPK signaling assays; cytokine/chemokine profiling Cellular & molecular immunology High 36693922
2023 Differential regulation of IL-17A versus IL-17F in psoriatic disease is mediated in part through opposing effects of STAT5/IL-2 signaling on each gene. IL-17A and IL-17F are predominantly expressed in distinct Th17 cell populations. A broad H3K4me3 region at the IL17A-F locus reflects transcriptional plasticity. Higher IL17F expression is linked to greater cell proliferation. Single-cell RNA sequencing; novel cytokine-capture technique combined with chromatin immunoprecipitation sequencing (ChIP-seq) and RNA-seq; H3K4me3 profiling; STAT5 pathway modulation; functional proliferation assays The Journal of allergy and clinical immunology High 37244461
2016 FGF2 cooperates synergistically with IL-17A to activate ERK signaling and amplify cytokine/chemokine production in fibroblast-like synoviocytes. In the collagen-induced arthritis model, ectopic FGF2 expression exacerbated tissue inflammation in wild-type mice but this effect was largely abolished in Il17a−/− mice, establishing IL-17A as a required effector of FGF2-driven synovial inflammation. Recombinant cytokine co-stimulation of human FLS; ERK phosphorylation (Western blot); cytokine/chemokine multiplex assay; ectopic FGF2 expression in mouse joints; collagen-induced arthritis in Il17a−/− vs wild-type mice Scientific reports High 28765647
2016 IL-17A is a previously unrecognized downstream effector of IL-18 in neonatal sepsis; IL-18 administration increases IL-17A production by intestinal γδ T cells and Ly6G+ myeloid cells, and blocking IL-17A reduces IL-18-potentiated mortality in both neonatal sepsis and endotoxemia models. The deleterious axis was defined as IL-18/IL-1R1/IL-17A, as increased lethality depended on IL-1R1 signaling. IL-18-null neonatal mice; IL-18 replenishment; IL-17A neutralizing antibody treatment; flow cytometry for IL-17A+ cell populations; genome-wide blood mRNA analysis; survival studies Proceedings of the National Academy of Sciences High 27114524
2019 IL-17A induces M2 macrophage polarization (CCL17, CD206 markers) indirectly by first acting on endometriotic epithelial cells rather than directly on macrophages. In a syngeneic mouse model of endometriosis, IL-17A treatment increased peritoneal macrophage numbers with M2 phenotype. Co-culture of THP-1 macrophage-like cells with endometriotic epithelial cells; IL-17A stimulation; RT-PCR and flow cytometry for M2 markers; syngeneic mouse endometriosis model with IL-17A treatment; macrophage enumeration Frontiers in immunology Medium 32117261

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 IL-17 and Th17 Cells. Annual review of immunology 3931 19132915
2006 Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. The Journal of experimental medicine 1871 16982811
2007 Phenotypic and functional features of human Th17 cells. The Journal of experimental medicine 1514 17635957
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 Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nature immunology 1474 17486092
2002 Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. The Journal of biological chemistry 1396 12417590
1999 IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. The Journal of clinical investigation 1350 10225978
2009 Structure and signalling in the IL-17 receptor family. Nature reviews. Immunology 1205 19575028
1996 T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. The Journal of experimental medicine 1194 8676080
2012 Targeting IL-17 and TH17 cells in chronic inflammation. Nature reviews. Drug discovery 1121 23023676
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2007 Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. The American journal of pathology 927 18156204
2008 Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 909 18337720
2009 The IL-23/Th17 axis in the immunopathogenesis of psoriasis. The Journal of investigative dermatology 884 19322214
2011 Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation. Immunity 872 21982596
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2011 Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science (New York, N.Y.) 802 21350122
2011 Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. Journal of immunology (Baltimore, Md. : 1950) 753 21606249
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
1999 Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways. Journal of immunology (Baltimore, Md. : 1950) 669 9973514
1995 Human IL-17: a novel cytokine derived from T cells. Journal of immunology (Baltimore, Md. : 1950) 664 7499828
2004 The human plasma proteome: a nonredundant list developed by combination of four separate sources. Molecular & cellular proteomics : MCP 658 14718574
2008 Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. Journal of immunology (Baltimore, Md. : 1950) 628 19050297
2017 IL-17 Signaling: The Yin and the Yang. Trends in immunology 626 28254169
2008 Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood 616 18617638
2009 Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proceedings of the National Academy of Sciences of the United States of America 590 19273860
2008 Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor. The Journal of experimental medicine 587 18663128
2008 Th17 cell differentiation: the long and winding road. Immunity 558 18400187
1993 CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene. Journal of immunology (Baltimore, Md. : 1950) 555 8390535
2013 Human inflammatory dendritic cells induce Th17 cell differentiation. Immunity 545 23352235
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