{"gene":"IL17A","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1993,"finding":"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.","method":"cDNA library subtraction, differential screening, sequence analysis, radioactive in situ hybridization","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — original cloning paper with multiple molecular methods; foundational discovery","pmids":["8390535"],"is_preprint":false},{"year":1995,"finding":"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.","method":"cDNA cloning, recombinant protein expression in CV1/EBNA cells, cytokine ELISA, FACS","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — direct functional characterization with recombinant protein; foundational cloning and activity paper","pmids":["7499828"],"is_preprint":false},{"year":1996,"finding":"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.","method":"Recombinant protein expression, co-culture assays, cytokine ELISA, CD34+ progenitor differentiation assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 — reconstituted functional activity with recombinant homodimer across multiple cell types; replicated in multiple assays","pmids":["8676080"],"is_preprint":false},{"year":1999,"finding":"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.","method":"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","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 — reconstituted system with multiple pharmacological inhibitors and functional readouts; mechanistic dissection across cell types","pmids":["10225978"],"is_preprint":false},{"year":1999,"finding":"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.","method":"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":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 — both in vitro reconstitution and in vivo model with antibody neutralization; mechanism fully delineated","pmids":["9973514"],"is_preprint":false},{"year":2002,"finding":"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).","method":"Cytokine stimulation of murine memory T cells; ELISA for IL-17 and IL-17F; comparison of IL-23 vs IL-12 effects","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — defined upstream regulatory signal for IL-17A production; independently replicated","pmids":["12417590"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Th17 cell differentiation assays; intracellular cytokine staining; keratinocyte stimulation with recombinant cytokines; RT-PCR for antimicrobial peptides","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1–2 — co-expression demonstrated in vitro and in vivo; functional synergy confirmed with recombinant cytokines on primary cells","pmids":["16982811"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Act1 knockout mice; domain deletion/mapping analysis; IL-17R co-immunoprecipitation; EAE and colitis models","journal":"Cytokine","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in vivo combined with domain mapping of Act1-IL-17R interaction; published in multiple independent contexts","pmids":["18061473"],"is_preprint":false},{"year":2009,"finding":"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.","method":"X-ray crystallography at 2.6 Å; H/D exchange mass spectrometry; site-directed mutagenesis; cell-based neutralization assay","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis validation and orthogonal HDX-MS confirmation","pmids":["19835883"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Domain functional analysis, genetic knockouts, signaling pathway assays (NF-κB, MAPK reporters)","journal":"Nature reviews. Immunology","confidence":"High","confidence_rationale":"Tier 2 — comprehensive review synthesizing multiple independent experimental studies defining the SEFIR-Act1 signaling axis","pmids":["19575028"],"is_preprint":false},{"year":2010,"finding":"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.","method":"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":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — combined in vivo knockout phenotype with in vitro mechanistic studies across multiple readouts","pmids":["21037091"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Immunohistochemistry and immunofluorescence of psoriatic skin biopsies; cell density quantification; stimulation of primary mast cells with IL-23 and IL-1β; ET visualization","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — direct protein localization in primary human tissue combined with functional in vitro stimulation; large n; paradigm-shifting finding independently replicated","pmids":["21606249"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Genetic knockout mice (Tcrd−/−, Tcra−/−, Il17ra−/−); IL-23 intradermal injection model; imiquimod-induced skin pathology model; flow cytometry; immunohistochemistry of human psoriatic skin","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic knockout strains with in vivo epistasis; confirmed in human psoriasis tissue","pmids":["21982596"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Genetic sequencing; receptor-ligand binding assays; functional cell stimulation assays with homo- and heterodimers; patient phenotypic characterization","journal":"Science","confidence":"High","confidence_rationale":"Tier 1–2 — human genetics combined with functional receptor-ligand assays; dissects IL-17A vs IL-17F specificity","pmids":["21350122"],"is_preprint":false},{"year":2016,"finding":"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.","method":"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","journal":"Experimental & molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — in vitro knockdown + in vivo injection model with multiple mechanistic readouts","pmids":["27980343"],"is_preprint":false},{"year":2019,"finding":"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.","method":"MIA mouse model; direct stereotactic IL-17A injection into S1DZ; conditional neuron-specific IL-17Ra knockout; social behavior assays; in vivo cytokine measurement; electrophysiology","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — gain-of-function (direct CNS delivery) and loss-of-function (conditional neuron-specific receptor KO) with behavioral readouts; multiple genetic models","pmids":["31853066"],"is_preprint":false},{"year":2019,"finding":"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).","method":"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","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — conditional knockout in relevant cell type with multiple orthogonal metabolic and functional readouts","pmids":["30962593"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Cryo-electron microscopy; single-molecule imaging; cell-based signaling assays; structure-function mutagenesis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structures of multiple complexes with functional validation; defines receptor assembly architecture","pmids":["35863378"],"is_preprint":false},{"year":2016,"finding":"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.","method":"NMR and X-ray crystallography of peptide–IL-17A complexes; SPR binding assays; cell-based IL-17A neutralization assay; structure-guided medicinal chemistry","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 — structural determination combined with functional neutralization assays","pmids":["27527709"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation; genetic knockouts; reporter assays for NF-κB and MAPK; mRNA stability assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — synthesizes multiple independent experimental studies; some findings from single labs","pmids":["31316496"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Primary human islet stimulation; RNA interference (STAT1 knockdown); STAT1 knockout mouse islets; RT-PCR; ELISA; nuclear dye viability assay","journal":"Diabetologia","confidence":"High","confidence_rationale":"Tier 2 — RNAi knockdown replicated in mouse genetic knockout; multiple readouts in primary human tissue","pmids":["24352375"],"is_preprint":false},{"year":2014,"finding":"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.","method":"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","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 — direct kinase activation (phospho-Western) combined with functional differentiation assay; single laboratory","pmids":["25557204"],"is_preprint":false},{"year":2018,"finding":"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.","method":"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","journal":"Digestive diseases and sciences","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro dose-response with in vivo antibody blockade; single laboratory; moderate mechanistic depth","pmids":["30097894"],"is_preprint":false},{"year":2023,"finding":"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.","method":"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","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — direct biochemical interaction (Co-IP), site-specific PTM (deacetylation at K192), ChIP at promoter, and in vivo conditional KO phenotype","pmids":["38135684"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation; competitive binding assays; FXYD3 conditional keratinocyte knockout; IMQ-induced psoriasis mouse model; NF-κB and MAPK signaling assays; cytokine/chemokine profiling","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with competitive binding mechanistic dissection + in vivo genetic model; multiple orthogonal approaches","pmids":["36693922"],"is_preprint":false},{"year":2023,"finding":"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.","method":"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","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 1–2 — multi-omic approach (scRNA-seq, ChIP-seq, RNA-seq) with functional readouts; chromatin-level mechanistic dissection","pmids":["37244461"],"is_preprint":false},{"year":2016,"finding":"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.","method":"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","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — in vitro synergy mechanistically confirmed; in vivo epistasis with IL-17A knockout validates requirement","pmids":["28765647"],"is_preprint":false},{"year":2016,"finding":"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.","method":"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","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout + antibody neutralization + cellular source identification; multiple in vivo readouts","pmids":["27114524"],"is_preprint":false},{"year":2019,"finding":"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.","method":"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","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 3 — co-culture system with in vivo confirmation; indirect mechanism inferred rather than directly probed","pmids":["32117261"],"is_preprint":false}],"current_model":"IL-17A is a disulfide-linked homodimer (cystine-knot fold) secreted by Th17 cells, γδ T cells, mast cells, and neutrophils that signals through an IL-17RA/IL-17RC heterodimer assembled in a 'tip-to-tip' architecture; the proximal adaptor Act1 (recruited via SEFIR–SEFIR domain interaction) engages TRAF proteins (especially TRAF6) to activate NF-κB, MAPK, and C/EBP pathways, inducing IL-6, IL-8, G-CSF, antimicrobial peptides, and CXC chemokines in stromal and epithelial cells; IκBζ and STAT1 serve as additional downstream transducers in specific cell types; IL-17A drives osteoclastogenesis indirectly through osteoblast RANKL/PGE2 upregulation, recruits neutrophils via CXC chemokine release from airway epithelium, inhibits adipogenesis and glucose uptake, promotes metabolic reprogramming of lymph node stromal cells through CPT1A induction, and acts directly on CNS neurons (via IL-17Ra) to modulate sociability, with its transcription regulated epigenetically by SIRT6-mediated RORγt deacetylation at K192 and by STAT5 signaling at the IL17A-F locus."},"narrative":{"teleology":[{"year":1993,"claim":"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","pmids":["8390535"],"confidence":"High","gaps":["Protein structure unknown","Receptor unidentified","Biological function of the secreted protein not yet determined"]},{"year":1996,"claim":"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","pmids":["7499828","8676080"],"confidence":"High","gaps":["Receptor identity unknown","Signaling pathway not mapped","In vivo relevance not yet tested"]},{"year":1999,"claim":"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","pmids":["10225978","9973514"],"confidence":"High","gaps":["Receptor subunit composition still undefined","Intracellular signaling cascade not yet identified","Source T cell subset not characterized"]},{"year":2002,"claim":"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","pmids":["12417590"],"confidence":"High","gaps":["Th17 lineage not yet formally defined","Transcription factors controlling IL-17A expression unknown","Role of TGF-β not yet established"]},{"year":2006,"claim":"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","pmids":["16982811"],"confidence":"High","gaps":["Receptor complex composition not yet resolved","Relative contribution of IL-17A versus IL-17F in vivo unclear"]},{"year":2007,"claim":"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","pmids":["18061473","19575028"],"confidence":"High","gaps":["TRAF specificity downstream of Act1 not fully dissected","Role of IL-17RC as obligate co-receptor not yet structurally proven"]},{"year":2009,"claim":"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","pmids":["19835883"],"confidence":"High","gaps":["Full receptor complex structure not yet determined","IL-17A/F heterodimer structure unresolved"]},{"year":2011,"claim":"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","pmids":["21606249","21982596","21350122"],"confidence":"High","gaps":["Relative contribution of each cellular source across tissues not quantified","Whether IL-17A and IL-17F are functionally redundant in antifungal defense remains unclear"]},{"year":2013,"claim":"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","pmids":["24352375"],"confidence":"High","gaps":["Whether STAT1 activation is direct or requires Act1/TRAF machinery is unclear","Generalizability beyond pancreatic islets not established"]},{"year":2016,"claim":"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","pmids":["27527709"],"confidence":"High","gaps":["In vivo pharmacokinetics and efficacy of macrocyclic antagonists not demonstrated","Selectivity over IL-17A/F heterodimer not addressed"]},{"year":2019,"claim":"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","pmids":["31853066","30962593"],"confidence":"High","gaps":["Neuronal signaling intermediates downstream of IL-17Ra in cortex not identified","Whether FRC metabolic reprogramming is conserved across all secondary lymphoid organs is unknown"]},{"year":2022,"claim":"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","pmids":["35863378"],"confidence":"High","gaps":["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"]},{"year":2023,"claim":"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","pmids":["38135684","37244461","36693922"],"confidence":"High","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"High","gaps":["Cytoplasmic signaling complex structure unresolved","IL-17A/F heterodimer receptor complex not structurally characterized","Neuronal downstream signaling unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,2,4,8,17,18]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[9,17]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,2,8]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,4,6,7,9,11,12,13,14,19,24,27]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,9,14,17,19,24]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,10,14,20,22]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[17]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[15]}],"complexes":["IL-17A homodimer","IL-17A–IL-17RA–IL-17RC ternary signaling complex"],"partners":["IL17RA","IL17RC","TRAF6IP2","TRAF6","TRAF3","IL22","FXYD3"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"Q16552","full_name":"Interleukin-17A","aliases":["Cytotoxic T-lymphocyte-associated antigen 8","CTLA-8"],"length_aa":155,"mass_kda":17.5,"function":"Effector cytokine of innate and adaptive immune system involved in antimicrobial host defense and maintenance of tissue integrity (PubMed:24120361). Signals via IL17RA-IL17RC heterodimeric receptor complex, triggering homotypic interaction of IL17RA and IL17RC chains with TRAF3IP2 adapter. This leads to downstream TRAF6-mediated activation of NF-kappa-B and MAPkinase pathways ultimately resulting in transcriptional activation of cytokines, chemokines, antimicrobial peptides and matrix metalloproteinases, with potential strong immune inflammation (PubMed:17911633, PubMed:18684971, PubMed:19825828, PubMed:21350122, PubMed:24120361, PubMed:8676080). Plays an important role in connecting T cell-mediated adaptive immunity and acute inflammatory response to destroy extracellular bacteria and fungi. As a signature effector cytokine of T-helper 17 cells (Th17), primarily induces neutrophil activation and recruitment at infection and inflammatory sites (By similarity). In airway epithelium, mediates neutrophil chemotaxis via induction of CXCL1 and CXCL5 chemokines (By similarity). In secondary lymphoid organs, contributes to germinal center formation by regulating the chemotactic response of B cells to CXCL12 and CXCL13, enhancing retention of B cells within the germinal centers, B cell somatic hypermutation rate and selection toward plasma cells (By similarity). Effector cytokine of a subset of gamma-delta T cells that functions as part of an inflammatory circuit downstream IL1B, TLR2 and IL23A-IL12B to promote neutrophil recruitment for efficient bacterial clearance (By similarity). Effector cytokine of innate immune cells including invariant natural killer cell (iNKT) and group 3 innate lymphoid cells that mediate initial neutrophilic inflammation (By similarity). Involved in the maintenance of the integrity of epithelial barriers during homeostasis and pathogen infection (PubMed:21350122). Upon acute injury, has a direct role in epithelial barrier formation by regulating OCLN localization and tight junction biogenesis (By similarity). As part of the mucosal immune response induced by commensal bacteria, enhances host's ability to resist pathogenic bacterial and fungal infections by promoting neutrophil recruitment and antimicrobial peptides release (By similarity). In synergy with IL17F, mediates the production of antimicrobial beta-defensins DEFB1, DEFB103A, and DEFB104A by mucosal epithelial cells, limiting the entry of microbes through the epithelial barriers (By similarity). Involved in antiviral host defense through various mechanisms (By similarity). Enhances immunity against West Nile virus by promoting T cell cytotoxicity (By similarity). May play a beneficial role in influenza A virus (H5N1) infection by enhancing B cell recruitment and immune response in the lung (By similarity). Contributes to influenza A virus (H1N1) clearance by driving the differentiation of B-1a B cells, providing for production of virus-specific IgM antibodies at first line of host defense (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q16552/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL17A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL17A","total_profiled":1310},"omim":[{"mim_id":"616622","title":"IMMUNODEFICIENCY 42; IMD42","url":"https://www.omim.org/entry/616622"},{"mim_id":"616445","title":"CANDIDIASIS, FAMILIAL, 9; CANDF9","url":"https://www.omim.org/entry/616445"},{"mim_id":"616115","title":"FAMILIAL COLD AUTOINFLAMMATORY SYNDROME 4; FCAS4","url":"https://www.omim.org/entry/616115"},{"mim_id":"616005","title":"IMMUNODEFICIENCY 36 WITH LYMPHOPROLIFERATION; IMD36","url":"https://www.omim.org/entry/616005"},{"mim_id":"615816","title":"IMMUNODEFICIENCY 23; IMD23","url":"https://www.omim.org/entry/615816"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":1.3}],"url":"https://www.proteinatlas.org/search/IL17A"},"hgnc":{"alias_symbol":["IL-17A","IL-17"],"prev_symbol":["CTLA8","IL17"]},"alphafold":{"accession":"Q16552","domains":[{"cath_id":"2.10.90.10","chopping":"66-155","consensus_level":"medium","plddt":94.61,"start":66,"end":155}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16552","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16552-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16552-F1-predicted_aligned_error_v6.png","plddt_mean":84.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL17A","jax_strain_url":"https://www.jax.org/strain/search?query=IL17A"},"sequence":{"accession":"Q16552","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16552.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16552/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16552"}},"corpus_meta":[{"pmid":"19132915","id":"PMC_19132915","title":"IL-17 and Th17 Cells.","date":"2009","source":"Annual review of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19132915","citation_count":3931,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19575028","id":"PMC_19575028","title":"Structure and signalling in the IL-17 receptor family.","date":"2009","source":"Nature reviews. Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19575028","citation_count":1205,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23023676","id":"PMC_23023676","title":"Targeting IL-17 and TH17 cells in chronic inflammation.","date":"2012","source":"Nature reviews. Drug discovery","url":"https://pubmed.ncbi.nlm.nih.gov/23023676","citation_count":1121,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7499828","id":"PMC_7499828","title":"Human IL-17: a novel cytokine derived from T cells.","date":"1995","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/7499828","citation_count":664,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28254169","id":"PMC_28254169","title":"IL-17 Signaling: The Yin and the Yang.","date":"2017","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28254169","citation_count":626,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24011563","id":"PMC_24011563","title":"IL-17 family: cytokines, receptors and signaling.","date":"2013","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/24011563","citation_count":470,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31745337","id":"PMC_31745337","title":"IL-17 receptor-based signaling and implications for disease.","date":"2019","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31745337","citation_count":429,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26038490","id":"PMC_26038490","title":"IL-17 cytokines in immunity and inflammation.","date":"2013","source":"Emerging microbes & infections","url":"https://pubmed.ncbi.nlm.nih.gov/26038490","citation_count":422,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30127781","id":"PMC_30127781","title":"The IL-17 Family of Cytokines in Psoriasis: IL-17A and Beyond.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30127781","citation_count":377,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27411590","id":"PMC_27411590","title":"Metabolic Inflammation-Associated IL-17A Causes Non-alcoholic Steatohepatitis and Hepatocellular Carcinoma.","date":"2016","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/27411590","citation_count":337,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21037091","id":"PMC_21037091","title":"IL-17 regulates adipogenesis, glucose homeostasis, and obesity.","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21037091","citation_count":309,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37816755","id":"PMC_37816755","title":"The IL-17 family in diseases: from bench to bedside.","date":"2023","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37816755","citation_count":299,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19767566","id":"PMC_19767566","title":"Protumor vs antitumor functions of IL-17.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19767566","citation_count":295,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18701318","id":"PMC_18701318","title":"An overview of IL-17 function and signaling.","date":"2008","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/18701318","citation_count":275,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15577820","id":"PMC_15577820","title":"IL-17 cytokine family.","date":"2004","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15577820","citation_count":260,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23253932","id":"PMC_23253932","title":"Effect of IL-17A blockade with secukinumab in autoimmune diseases.","date":"2012","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/23253932","citation_count":254,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21852080","id":"PMC_21852080","title":"Recent advances in the IL-17 cytokine family.","date":"2011","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21852080","citation_count":230,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32358580","id":"PMC_32358580","title":"COVID-19: a case for inhibiting IL-17?","date":"2020","source":"Nature reviews. Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32358580","citation_count":222,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31853066","id":"PMC_31853066","title":"IL-17a promotes sociability in mouse models of neurodevelopmental disorders.","date":"2019","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/31853066","citation_count":219,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18164424","id":"PMC_18164424","title":"Production and functions of IL-17 in microglia.","date":"2007","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/18164424","citation_count":212,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32955487","id":"PMC_32955487","title":"IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis.","date":"2020","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/32955487","citation_count":207,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21197451","id":"PMC_21197451","title":"Role of IL-17 and Th17 cells in liver diseases.","date":"2010","source":"Clinical & developmental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21197451","citation_count":206,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17048275","id":"PMC_17048275","title":"Vaccination against IL-17 suppresses autoimmune arthritis and encephalomyelitis.","date":"2006","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17048275","citation_count":167,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28860146","id":"PMC_28860146","title":"IL-17 in the lung: the good, the bad, and the ugly.","date":"2017","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28860146","citation_count":153,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31129129","id":"PMC_31129129","title":"IL-17A inhibition by secukinumab induces early clinical, histopathologic, and molecular resolution of psoriasis.","date":"2019","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31129129","citation_count":150,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21084215","id":"PMC_21084215","title":"IL-17 in obesity and adipogenesis.","date":"2010","source":"Cytokine & growth factor reviews","url":"https://pubmed.ncbi.nlm.nih.gov/21084215","citation_count":149,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26780388","id":"PMC_26780388","title":"Proinflammatory T cells and IL-17 stimulate osteoblast differentiation.","date":"2016","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/26780388","citation_count":148,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11401524","id":"PMC_11401524","title":"Expression of IL-17 mRNA in ovarian cancer.","date":"2001","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11401524","citation_count":140,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22362575","id":"PMC_22362575","title":"Role of IL-17 in psoriasis and psoriatic arthritis.","date":"2013","source":"Clinical reviews in allergy & immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22362575","citation_count":130,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30006601","id":"PMC_30006601","title":"IL-17 in the immunopathogenesis of spondyloarthritis.","date":"2018","source":"Nature reviews. Rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/30006601","citation_count":119,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32379344","id":"PMC_32379344","title":"IL-17 in inflammatory skin diseases psoriasis and hidradenitis suppurativa.","date":"2020","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32379344","citation_count":117,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17027518","id":"PMC_17027518","title":"The IL-17 cytokine family.","date":"2006","source":"Vitamins and hormones","url":"https://pubmed.ncbi.nlm.nih.gov/17027518","citation_count":116,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25039885","id":"PMC_25039885","title":"Cellular sources of IL-17 in psoriasis: a paradigm shift?","date":"2014","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/25039885","citation_count":112,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18832032","id":"PMC_18832032","title":"The IL-17 cytokine family and their role in allergic inflammation.","date":"2008","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18832032","citation_count":111,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32117261","id":"PMC_32117261","title":"IL-17A Modulates Peritoneal Macrophage Recruitment and M2 Polarization in Endometriosis.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32117261","citation_count":104,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31227819","id":"PMC_31227819","title":"Systemic effects of IL-17 in inflammatory arthritis.","date":"2019","source":"Nature reviews. Rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/31227819","citation_count":103,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28455196","id":"PMC_28455196","title":"Maternal IL-17A in autism.","date":"2017","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/28455196","citation_count":99,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27109641","id":"PMC_27109641","title":"T cells and IL-17 in lupus nephritis.","date":"2016","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/27109641","citation_count":96,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27263531","id":"PMC_27263531","title":"IL-17A mediates inflammatory and tissue remodelling events in early human tendinopathy.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27263531","citation_count":96,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27114524","id":"PMC_27114524","title":"Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27114524","citation_count":95,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20177959","id":"PMC_20177959","title":"The IL-17 family cytokines in immunity and disease.","date":"2010","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20177959","citation_count":93,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29371568","id":"PMC_29371568","title":"The Role of IL-17 in Protection against Mucosal Candida Infections.","date":"2017","source":"Journal of fungi (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/29371568","citation_count":88,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30962593","id":"PMC_30962593","title":"IL-17 metabolically reprograms activated fibroblastic reticular cells for proliferation and survival.","date":"2019","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30962593","citation_count":83,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24907519","id":"PMC_24907519","title":"IL-17 inhibits osteoblast differentiation and bone regeneration in rat.","date":"2014","source":"Archives of oral biology","url":"https://pubmed.ncbi.nlm.nih.gov/24907519","citation_count":80,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17981475","id":"PMC_17981475","title":"Regulation of IL-17 production in human lymphocytes.","date":"2007","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/17981475","citation_count":79,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31316496","id":"PMC_31316496","title":"TRAF Regulation of IL-17 Cytokine Signaling.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31316496","citation_count":77,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27980343","id":"PMC_27980343","title":"IL-17A exacerbates diabetic retinopathy by impairing Müller cell function via Act1 signaling.","date":"2016","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27980343","citation_count":76,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34853779","id":"PMC_34853779","title":"The Role of IL-17 Cytokines in Psoriasis.","date":"2021","source":"ImmunoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34853779","citation_count":75,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31603358","id":"PMC_31603358","title":"Anti IL-17 in psoriasis.","date":"2019","source":"Expert review of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31603358","citation_count":74,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23604380","id":"PMC_23604380","title":"IL-17 in lung disease: friend or foe?","date":"2013","source":"Thorax","url":"https://pubmed.ncbi.nlm.nih.gov/23604380","citation_count":74,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19835883","id":"PMC_19835883","title":"Structure of IL-17A in complex with a potent, fully human neutralizing antibody.","date":"2009","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19835883","citation_count":71,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23562549","id":"PMC_23562549","title":"IL-17 in psoriasis: implications for therapy and cardiovascular co-morbidities.","date":"2013","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/23562549","citation_count":66,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21134467","id":"PMC_21134467","title":"Genomics of fish IL-17 ligand and receptors: a review.","date":"2010","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21134467","citation_count":65,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35863378","id":"PMC_35863378","title":"Organizing structural principles of the IL-17 ligand-receptor axis.","date":"2022","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/35863378","citation_count":61,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30097894","id":"PMC_30097894","title":"IL-17A Promotes Initiation and Development of Intestinal Fibrosis Through EMT.","date":"2018","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30097894","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28222445","id":"PMC_28222445","title":"Blocking IL-17A Alleviates Diabetic Retinopathy in Rodents.","date":"2017","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28222445","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18061473","id":"PMC_18061473","title":"Act1 modulates autoimmunity through its dual functions in CD40L/BAFF and IL-17 signaling.","date":"2007","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/18061473","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26076201","id":"PMC_26076201","title":"Correlation of IL-17 Level in Synovia and Severity of Knee Osteoarthritis.","date":"2015","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/26076201","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19079228","id":"PMC_19079228","title":"Regulatory T cells and the induction of IL-17.","date":"2008","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19079228","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27206706","id":"PMC_27206706","title":"Cross-Disease Transcriptomics: Unique IL-17A Signaling in Psoriasis Lesions and an Autoimmune PBMC Signature.","date":"2016","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/27206706","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37291218","id":"PMC_37291218","title":"Targeting lymphoid-derived IL-17 signaling to delay skin aging.","date":"2023","source":"Nature aging","url":"https://pubmed.ncbi.nlm.nih.gov/37291218","citation_count":54,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24552504","id":"PMC_24552504","title":"The role of IL-17 in psoriasis.","date":"2014","source":"The Journal of dermatological treatment","url":"https://pubmed.ncbi.nlm.nih.gov/24552504","citation_count":54,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28919455","id":"PMC_28919455","title":"Is there a role for IL-17 in the pathogenesis of systemic sclerosis?","date":"2017","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/28919455","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26236331","id":"PMC_26236331","title":"Regulation of IL-17 in autoimmune diseases by transcriptional factors and microRNAs.","date":"2015","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26236331","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22876724","id":"PMC_22876724","title":"IL-17, neutrophil activation and muscle damage following endurance exercise.","date":"2012","source":"Exercise immunology review","url":"https://pubmed.ncbi.nlm.nih.gov/22876724","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26491201","id":"PMC_26491201","title":"Characterization of Lamprey IL-17 Family Members and Their Receptors.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/26491201","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26457610","id":"PMC_26457610","title":"The IL-23 to IL-17 cascade inflammation-related cancers.","date":"2015","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/26457610","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30576610","id":"PMC_30576610","title":"The advent of IL-17A blockade in ankylosing spondylitis: secukinumab, ixekizumab and beyond.","date":"2019","source":"Expert review of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30576610","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34429872","id":"PMC_34429872","title":"Role of IL-17 in atopy-A systematic review.","date":"2021","source":"Clinical and translational allergy","url":"https://pubmed.ncbi.nlm.nih.gov/34429872","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25398490","id":"PMC_25398490","title":"IL-17 and infections.","date":"2014","source":"Actas dermo-sifiliograficas","url":"https://pubmed.ncbi.nlm.nih.gov/25398490","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27576555","id":"PMC_27576555","title":"Targeting IL-17 in autoimmunity and inflammation.","date":"2016","source":"Archives of pharmacal research","url":"https://pubmed.ncbi.nlm.nih.gov/27576555","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27527709","id":"PMC_27527709","title":"Binding site elucidation and structure guided design of macrocyclic IL-17A antagonists.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27527709","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38806624","id":"PMC_38806624","title":"Targeting STING in dendritic cells alleviates psoriatic inflammation by suppressing IL-17A production.","date":"2024","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38806624","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38802947","id":"PMC_38802947","title":"IL-17 in wound repair: bridging acute and chronic responses.","date":"2024","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/38802947","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27856660","id":"PMC_27856660","title":"Effect of IL-17 receptor A blockade with brodalumab in inflammatory diseases.","date":"2016","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/27856660","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25557204","id":"PMC_25557204","title":"IL-17A activates ERK1/2 and enhances differentiation of oligodendrocyte progenitor cells.","date":"2014","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/25557204","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25398488","id":"PMC_25398488","title":"Pathogenic role of IL-17 in psoriasis and psoriatic arthritis.","date":"2014","source":"Actas dermo-sifiliograficas","url":"https://pubmed.ncbi.nlm.nih.gov/25398488","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24352375","id":"PMC_24352375","title":"IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets.","date":"2013","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/24352375","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18446062","id":"PMC_18446062","title":"IL-17 induces the production of IL-16 in rheumatoid arthritis.","date":"2008","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18446062","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28633806","id":"PMC_28633806","title":"IL-17 for therapy.","date":"2017","source":"Journal of dermatological science","url":"https://pubmed.ncbi.nlm.nih.gov/28633806","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23886112","id":"PMC_23886112","title":"Inhibition of IL-17 as a pharmacological approach for IBD.","date":"2013","source":"International reviews of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23886112","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38135684","id":"PMC_38135684","title":"Epithelial SIRT6 governs IL-17A pathogenicity and drives allergic airway inflammation and remodeling.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38135684","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35603223","id":"PMC_35603223","title":"The Yin and Yang of IL-17 in Systemic Sclerosis.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35603223","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29813133","id":"PMC_29813133","title":"IL-17 can be protective or deleterious in murine pneumococcal pneumonia.","date":"2018","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/29813133","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25054133","id":"PMC_25054133","title":"Poststroke neuropsychiatric symptoms: relationships with IL-17 and oxidative stress.","date":"2014","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/25054133","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37884768","id":"PMC_37884768","title":"Th17 Cells and IL-17A in Ischemic Stroke.","date":"2023","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/37884768","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29308283","id":"PMC_29308283","title":"Targeting IL-17 in psoriatic arthritis.","date":"2017","source":"European journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/29308283","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32516792","id":"PMC_32516792","title":"IL-17D: A Less Studied Cytokine of IL-17 Family.","date":"2020","source":"International archives of allergy and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32516792","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35387016","id":"PMC_35387016","title":"Pharmacological Rationale for Targeting IL-17 in Asthma.","date":"2021","source":"Frontiers in allergy","url":"https://pubmed.ncbi.nlm.nih.gov/35387016","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28765647","id":"PMC_28765647","title":"FGF2 cooperates with IL-17 to promote autoimmune inflammation.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28765647","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32002770","id":"PMC_32002770","title":"The Interrelationship Between Diabetes, IL-17 and Bone Loss.","date":"2020","source":"Current osteoporosis reports","url":"https://pubmed.ncbi.nlm.nih.gov/32002770","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37244461","id":"PMC_37244461","title":"Differential regulation of IL-17A and IL-17F via STAT5 contributes to psoriatic disease.","date":"2023","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37244461","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31402691","id":"PMC_31402691","title":"The Role of IL-17 in Papulopustular Rosacea and Future Directions.","date":"2019","source":"Journal of cutaneous medicine and surgery","url":"https://pubmed.ncbi.nlm.nih.gov/31402691","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22019285","id":"PMC_22019285","title":"IL-17 producing cells in host defense and atopy.","date":"2011","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22019285","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27107665","id":"PMC_27107665","title":"IL-17A promotes microglial activation and neuroinflammation in mouse models of intracerebral haemorrhage.","date":"2016","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27107665","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35838944","id":"PMC_35838944","title":"A comprehensive network map of IL-17A signaling pathway.","date":"2022","source":"Journal of cell communication and signaling","url":"https://pubmed.ncbi.nlm.nih.gov/35838944","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24571471","id":"PMC_24571471","title":"IL-17A regulates Eimeria tenella schizont maturation and migration in avian coccidiosis.","date":"2014","source":"Veterinary research","url":"https://pubmed.ncbi.nlm.nih.gov/24571471","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36693922","id":"PMC_36693922","title":"FXYD3 enhances IL-17A signaling to promote psoriasis by competitively binding TRAF3 in keratinocytes.","date":"2023","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36693922","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32285564","id":"PMC_32285564","title":"Brodalumab: A new way to inhibit IL-17 in psoriasis.","date":"2020","source":"Dermatologic therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32285564","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19386512","id":"PMC_19386512","title":"Barrier immunity and IL-17.","date":"2009","source":"Seminars in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19386512","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16982811","id":"PMC_16982811","title":"Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides.","date":"2006","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16982811","citation_count":1871,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17635957","id":"PMC_17635957","title":"Phenotypic and functional features of human Th17 cells.","date":"2007","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17635957","citation_count":1514,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17486092","id":"PMC_17486092","title":"Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells.","date":"2007","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17486092","citation_count":1474,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12417590","id":"PMC_12417590","title":"Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12417590","citation_count":1396,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10225978","id":"PMC_10225978","title":"IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis.","date":"1999","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/10225978","citation_count":1350,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8676080","id":"PMC_8676080","title":"T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines.","date":"1996","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/8676080","citation_count":1194,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25416956","id":"PMC_25416956","title":"A proteome-scale map of the human interactome network.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25416956","citation_count":977,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18156204","id":"PMC_18156204","title":"Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis.","date":"2007","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/18156204","citation_count":927,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18337720","id":"PMC_18337720","title":"Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome.","date":"2008","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/18337720","citation_count":909,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19322214","id":"PMC_19322214","title":"The IL-23/Th17 axis in the immunopathogenesis of psoriasis.","date":"2009","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/19322214","citation_count":884,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21982596","id":"PMC_21982596","title":"Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation.","date":"2011","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/21982596","citation_count":872,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21350122","id":"PMC_21350122","title":"Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity.","date":"2011","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/21350122","citation_count":802,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21606249","id":"PMC_21606249","title":"Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis.","date":"2011","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21606249","citation_count":753,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9973514","id":"PMC_9973514","title":"Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways.","date":"1999","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9973514","citation_count":669,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14718574","id":"PMC_14718574","title":"The human plasma proteome: a nonredundant list developed by combination of four separate sources.","date":"2004","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/14718574","citation_count":658,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19050297","id":"PMC_19050297","title":"Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19050297","citation_count":628,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18617638","id":"PMC_18617638","title":"Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18617638","citation_count":616,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19273860","id":"PMC_19273860","title":"Identification of IL-17-producing FOXP3+ regulatory T cells in humans.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19273860","citation_count":590,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18663128","id":"PMC_18663128","title":"Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor.","date":"2008","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18663128","citation_count":587,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18400187","id":"PMC_18400187","title":"Th17 cell differentiation: the long and winding road.","date":"2008","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/18400187","citation_count":558,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8390535","id":"PMC_8390535","title":"CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene.","date":"1993","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8390535","citation_count":555,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23352235","id":"PMC_23352235","title":"Human inflammatory dendritic cells induce Th17 cell differentiation.","date":"2013","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/23352235","citation_count":545,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18591410","id":"PMC_18591410","title":"Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3.","date":"2008","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18591410","citation_count":543,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18432274","id":"PMC_18432274","title":"Possible pathogenic role of Th17 cells for atopic dermatitis.","date":"2008","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/18432274","citation_count":536,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20032993","id":"PMC_20032993","title":"Circulating Th17, Th22, and Th1 cells are increased in psoriasis.","date":"2009","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/20032993","citation_count":495,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":40910,"output_tokens":5103,"usd":0.099638},"stage2":{"model":"claude-opus-4-6","input_tokens":8772,"output_tokens":2975,"usd":0.177352},"total_usd":0.659306,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":53832,"output_tokens":8182,"usd":0.142113},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":12322,"output_tokens":3941,"usd":0.240203}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Human IL-17A (hIL-17) was cloned from a CD4+ T cell library; recombinant hIL-17 is secreted in glycosylated and nonglycosylated forms and induces IL-6 and IL-8 production and enhances ICAM-1 surface expression on human fibroblasts.\",\n      \"method\": \"cDNA cloning, recombinant protein expression, cytokine ELISA, flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — original cloning paper with direct functional assays; foundational study replicated by many subsequent labs\",\n      \"pmids\": [\"7499828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-17A signals through the IL-17RA receptor; the IL-17R family uses unique structural motifs (SEFIR domain) and proximal signaling mediators distinct from other cytokine families to mediate downstream events including NF-κB and MAPK activation.\",\n      \"method\": \"Structural/functional domain analysis, signaling pathway studies\",\n      \"journal\": \"Nature reviews. Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — comprehensive review consolidating multiple experimental studies; replicated across many labs\",\n      \"pmids\": [\"19575028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Act1 (adaptor protein) interacts with IL-17R through its C-terminal SEFIR domain and is a key positive signaling component for the IL-17 signaling pathway; Act1-deficient mice are resistant to Th17-dependent EAE and colitis.\",\n      \"method\": \"Genetic knockout mice, domain mapping, Co-IP, disease models\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with defined phenotype plus domain-level binding mechanism; replicated across labs\",\n      \"pmids\": [\"18061473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Crystal structure of IL-17A homodimer in complex with neutralizing antibody CAT-2200 Fab at 2.6 Å resolution revealed that IL-17A is a disulfide-linked homodimer with a cystine-knot fold; the epitope spans 12 residues from the quaternary structure with each Fab contacting both monomers; receptor binding cavity predicted on IL-17 family members.\",\n      \"method\": \"X-ray crystallography, hydrogen/deuterium exchange mass spectrometry, mutagenesis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure at 2.6 Å with orthogonal H/D exchange MS and mutagenesis validation\",\n      \"pmids\": [\"19835883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structures of IL-17A-IL-17RA binary and IL-17A-IL-17RA-IL-17RC ternary complexes revealed that IL-17A signals through a C2-symmetric ternary complex with a 'tip-to-tip' receptor-receptor interaction as the key organizing principle; IL-17RA serves dual roles—directly engaging IL-17A and functioning as a co-receptor.\",\n      \"method\": \"Cryo-electron microscopy, single-molecule imaging, cell-based signaling assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure plus single-molecule imaging and functional signaling validation in one study\",\n      \"pmids\": [\"35863378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL-17A signals through downstream pathways including NF-κB, MAPKs, and C/EBPs; the proximal adaptor Act1 is a common mediator for all IL-17 cytokine signaling and is required for IL-17-mediated host defense and autoimmune conditions.\",\n      \"method\": \"Signaling assays, genetic knockout models, in vitro pathway analysis\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal experimental approaches across multiple labs establishing Act1/NF-κB/MAPK pathway\",\n      \"pmids\": [\"24011563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17A directly acts on neurons in the primary somatosensory cortex dysgranular zone (S1DZ) via IL-17Ra expressed on neurons; direct intracranial delivery of IL-17A into S1DZ rescued social behavior deficits in mouse models of neurodevelopmental disorders, and ablation of IL-17Ra in S1DZ neurons eliminated LPS-induced behavioral rescue.\",\n      \"method\": \"Intracranial cytokine delivery, conditional receptor knockout in neurons, behavioral assays, neuronal activity recording\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct in vivo intervention with receptor-specific conditional KO and behavioral readout; multiple orthogonal approaches in one study\",\n      \"pmids\": [\"31853066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-17A exacerbates diabetic retinopathy by impairing Müller cell function via the Act1/TRAF6/IKK/NF-κB signaling pathway; Act1 knockdown or IKK inhibition blocked downstream IL-17A signaling activation and ameliorated retinal vascular damage.\",\n      \"method\": \"siRNA knockdown, kinase inhibition, in vitro Müller cell culture, intravitreal injection in mouse DR model\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pathway placement by loss-of-function (siRNA + inhibitor) with defined cellular phenotype replicated in vivo\",\n      \"pmids\": [\"27980343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17 signaling in fibroblastic reticular cells (FRCs) induces the transcriptional co-activator IκBζ, which mediates increased glucose uptake and upregulates CPT1A expression (rate-limiting enzyme of mitochondrial fatty acid oxidation), thereby reprogramming FRC metabolism to support proliferation and survival.\",\n      \"method\": \"Genetic IL-17R knockout, EAE and colitis models, metabolic assays, gene expression analysis\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined metabolic phenotype and identified IκBζ/CPT1A mechanism; multiple orthogonal methods\",\n      \"pmids\": [\"30962593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-17A increases proinflammatory chemokine expression and apoptosis in human pancreatic islets synergistically with IL-1β+IFN-γ; this effect requires STAT1, as STAT1 knockdown and STAT1 knockout mouse islets were protected from IL-17A+cytokine-induced apoptosis and specific chemokine expression.\",\n      \"method\": \"RNA interference, STAT1 KO mouse islets, RT-PCR, ELISA, cell viability assays\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with STAT1 KO validated in both human islets and mouse models with multiple readouts\",\n      \"pmids\": [\"24352375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17A is a previously unrecognized effector of IL-18-mediated injury in neonatal sepsis; IL-18 administration increased IL-17A production by intestinal γδT cells and Ly6G+ myeloid cells, and blocking IL-17A reduced IL-18-potentiated mortality.\",\n      \"method\": \"IL-18 null mice, cytokine blocking antibodies, flow cytometry, genome-wide mRNA analysis\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic null mice plus antibody blockade, but IL-17A pathway placement based on correlative genomics supported by functional intervention\",\n      \"pmids\": [\"27114524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-17A promotes initiation and development of intestinal fibrosis through induction of epithelial-mesenchymal transition (EMT), causing reduced E-cadherin and increased vimentin, snail, and α-SMA expression in intestinal epithelial cells; anti-IL-17A treatment alleviated fibrosis by reducing EMT in vivo.\",\n      \"method\": \"In vitro IEC-6 cell treatment, in vivo TNBS mouse model with anti-IL-17A antibody, RT-PCR, immunostaining\",\n      \"journal\": \"Digestive diseases and sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — defined EMT mechanism in vitro with in vivo confirmation by antibody blockade; single lab\",\n      \"pmids\": [\"30097894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-17A activates ERK1/2 within 15 minutes in oligodendrocyte progenitor cells (OPCs) and promotes their differentiation and maturation, including increased proteolipid protein expression in a cerebellar slice culture assay, alongside chemokine induction.\",\n      \"method\": \"Primary murine OPC culture, ERK1/2 phosphorylation assay, cerebellar slice culture, flow cytometry\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct kinase activation assay with functional differentiation readout; single lab\",\n      \"pmids\": [\"25557204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRAF proteins (TRAFs) mediate IL-17 receptor signaling by engaging downstream cellular machinery upon IL-17R activation, promoting NF-κB and other inflammatory pathways; TRAFs act as essential adaptors between IL-17R and downstream signaling cascades.\",\n      \"method\": \"Biochemical signaling studies, genetic models reviewed\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — consolidates multiple experimental studies on TRAF-IL-17R interaction; moderate evidence from multiple labs\",\n      \"pmids\": [\"31316496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-17 inhibits adipogenesis by suppressing adipocyte differentiation from 3T3-L1 preadipocytes in vitro, inhibiting expression of proadipogenic transcription factors, adipokines, and molecules involved in lipid and glucose metabolism; IL-17 also impairs glucose uptake in differentiated adipocytes.\",\n      \"method\": \"3T3-L1 preadipocyte differentiation assay, IL-17 KO mice, gene expression analysis, glucose uptake assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro mechanistic assays corroborated by IL-17 KO mouse phenotype; single lab with multiple methods\",\n      \"pmids\": [\"21037091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-17 induces IL-16 production specifically in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) in a dose-dependent manner, but not in OA-FLS; this effect is selective for IL-17 compared to IL-15, IL-1β, and IFN-γ.\",\n      \"method\": \"RT-PCR, real-time PCR, western blot, RA-FLS vs OA-FLS comparison\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — dose-response and cell-type specificity established; single lab with multiple methods\",\n      \"pmids\": [\"18446062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-17A promotes macrophage M2 polarization indirectly through interaction with endometriotic epithelial cells (not directly on macrophages), inducing M2 markers CCL17 and CD206; in vivo IL-17A treatment increased peritoneal macrophages with M2 phenotype.\",\n      \"method\": \"Co-culture system, syngeneic mouse model, flow cytometry, ELISA\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — indirect mechanism defined by co-culture showing epithelial cell requirement; in vitro and in vivo data from single lab\",\n      \"pmids\": [\"32117261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT6 directly interacts with RORγt and mediates RORγt deacetylation at lysine 192 via its PPXY motifs; SIRT6 promotes RORγt recruitment to the IL-17A gene promoter and enhances IL-17A transcription, thereby governing IL-17A pathogenicity in severe asthma.\",\n      \"method\": \"Conditional Sirt6 knockout mice, Co-IP, ChIP, SIRT6 inhibitor treatment, luciferase reporter assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — specific deacetylation site identified with domain mapping, ChIP showing promoter recruitment, conditional KO with in vivo phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"38135684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FXYD3 promotes the formation of the IL-17R-ACT1 complex by competitively binding TRAF3, thereby displacing TRAF3 from IL-17R and enhancing IL-17A signaling through NF-κB and MAPK pathways in keratinocytes; IL-17A induces FXYD3 expression, creating a positive regulatory loop.\",\n      \"method\": \"Co-IP, competitive binding assay, FXYD3 keratinocyte-specific deletion in IMQ psoriasis model, NF-κB/MAPK signaling assays\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP defining competitive TRAF3 binding mechanism, confirmed by in vivo conditional KO with defined inflammatory phenotype\",\n      \"pmids\": [\"36693922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-17A promotes microglial activation and neuroinflammation in intracerebral haemorrhage by activating MyD88, TRIF, IκBα, and NF-κBp65 signaling; IL-17A neutralizing antibody prevented cytokine expression (TNF-α, IL-1β, IL-6) and attenuated microglial activation.\",\n      \"method\": \"Autologous blood ICH mouse model, IL-17A neutralizing antibody, western blot for signaling molecules, brain water content measurement\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — defined NF-κB/MyD88 pathway by antibody blockade in vivo; single lab\",\n      \"pmids\": [\"27107665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FGF2 cooperates with IL-17A to synergistically induce ERK activation and production of cytokines and chemokines in fibroblast-like synoviocytes; in vivo, ectopic FGF2 expression exacerbated IL-17A-dependent arthritis in wild-type but not Il17a-/- mice, placing IL-17A downstream of FGF2-driven synovial inflammation.\",\n      \"method\": \"Human FLS stimulation assays, ERK phosphorylation, collagen-induced arthritis model in Il17a-/- mice\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis using Il17a KO mice with in vitro signaling assays; single lab\",\n      \"pmids\": [\"28765647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-17A and IL-17F expression is differentially regulated via STAT5/IL-2 signaling in psoriatic Th17 cells, with opposing effects on each gene; both isoforms are expressed predominantly in distinct cell populations, and IL-17F expression is linked to greater cell proliferation.\",\n      \"method\": \"Single-cell RNA sequencing, cytokine-capture technique combined with ChIP-seq and RNA-seq, H3K4me3 chromatin analysis\",\n      \"journal\": \"Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal genomic/epigenomic methods; single lab but rigorous multi-modal approach\",\n      \"pmids\": [\"37244461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Small-molecule macrocyclic ligands competitively bind to the IL-17A protein surface at the receptor-binding site; structure-guided design using binding site elucidation from linear peptide ligands yielded potent IL-17A antagonists that block IL-17RA engagement.\",\n      \"method\": \"Structural NMR/X-ray characterization, binding site mapping, cell-based neutralization assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — structure-guided design with binding site validation; single lab moderate evidence\",\n      \"pmids\": [\"27527709\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-17A is a disulfide-linked homodimer with a cystine-knot fold that signals through a C2-symmetric ternary complex with IL-17RA and IL-17RC (or other co-receptors) via a 'tip-to-tip' receptor architecture; upon receptor engagement, the adaptor Act1 (recruited via its SEFIR domain) activates TRAFs and downstream NF-κB, MAPK, and C/EBP pathways to drive proinflammatory gene expression, mRNA stabilization, and—in specific cell types such as FRCs—metabolic reprogramming through IκBζ and CPT1A, while transcription of IL-17A itself is governed epigenetically by SIRT6-mediated deacetylation of RORγt at K192 and post-translationally regulated by modulators such as FXYD3 that competitively displace TRAF3 from the IL-17R-ACT1 complex to amplify signaling.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"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.\",\n      \"method\": \"cDNA library subtraction, differential screening, sequence analysis, radioactive in situ hybridization\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original cloning paper with multiple molecular methods; foundational discovery\",\n      \"pmids\": [\"8390535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"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.\",\n      \"method\": \"cDNA cloning, recombinant protein expression in CV1/EBNA cells, cytokine ELISA, FACS\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct functional characterization with recombinant protein; foundational cloning and activity paper\",\n      \"pmids\": [\"7499828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"Recombinant protein expression, co-culture assays, cytokine ELISA, CD34+ progenitor differentiation assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted functional activity with recombinant homodimer across multiple cell types; replicated in multiple assays\",\n      \"pmids\": [\"8676080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted system with multiple pharmacological inhibitors and functional readouts; mechanistic dissection across cell types\",\n      \"pmids\": [\"10225978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — both in vitro reconstitution and in vivo model with antibody neutralization; mechanism fully delineated\",\n      \"pmids\": [\"9973514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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).\",\n      \"method\": \"Cytokine stimulation of murine memory T cells; ELISA for IL-17 and IL-17F; comparison of IL-23 vs IL-12 effects\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — defined upstream regulatory signal for IL-17A production; independently replicated\",\n      \"pmids\": [\"12417590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Th17 cell differentiation assays; intracellular cytokine staining; keratinocyte stimulation with recombinant cytokines; RT-PCR for antimicrobial peptides\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — co-expression demonstrated in vitro and in vivo; functional synergy confirmed with recombinant cytokines on primary cells\",\n      \"pmids\": [\"16982811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Act1 knockout mice; domain deletion/mapping analysis; IL-17R co-immunoprecipitation; EAE and colitis models\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in vivo combined with domain mapping of Act1-IL-17R interaction; published in multiple independent contexts\",\n      \"pmids\": [\"18061473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography at 2.6 Å; H/D exchange mass spectrometry; site-directed mutagenesis; cell-based neutralization assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis validation and orthogonal HDX-MS confirmation\",\n      \"pmids\": [\"19835883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Domain functional analysis, genetic knockouts, signaling pathway assays (NF-κB, MAPK reporters)\",\n      \"journal\": \"Nature reviews. Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — comprehensive review synthesizing multiple independent experimental studies defining the SEFIR-Act1 signaling axis\",\n      \"pmids\": [\"19575028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — combined in vivo knockout phenotype with in vitro mechanistic studies across multiple readouts\",\n      \"pmids\": [\"21037091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Immunohistochemistry and immunofluorescence of psoriatic skin biopsies; cell density quantification; stimulation of primary mast cells with IL-23 and IL-1β; ET visualization\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct protein localization in primary human tissue combined with functional in vitro stimulation; large n; paradigm-shifting finding independently replicated\",\n      \"pmids\": [\"21606249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic knockout mice (Tcrd−/−, Tcra−/−, Il17ra−/−); IL-23 intradermal injection model; imiquimod-induced skin pathology model; flow cytometry; immunohistochemistry of human psoriatic skin\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic knockout strains with in vivo epistasis; confirmed in human psoriasis tissue\",\n      \"pmids\": [\"21982596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic sequencing; receptor-ligand binding assays; functional cell stimulation assays with homo- and heterodimers; patient phenotypic characterization\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — human genetics combined with functional receptor-ligand assays; dissects IL-17A vs IL-17F specificity\",\n      \"pmids\": [\"21350122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro knockdown + in vivo injection model with multiple mechanistic readouts\",\n      \"pmids\": [\"27980343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"MIA mouse model; direct stereotactic IL-17A injection into S1DZ; conditional neuron-specific IL-17Ra knockout; social behavior assays; in vivo cytokine measurement; electrophysiology\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function (direct CNS delivery) and loss-of-function (conditional neuron-specific receptor KO) with behavioral readouts; multiple genetic models\",\n      \"pmids\": [\"31853066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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).\",\n      \"method\": \"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\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional knockout in relevant cell type with multiple orthogonal metabolic and functional readouts\",\n      \"pmids\": [\"30962593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-electron microscopy; single-molecule imaging; cell-based signaling assays; structure-function mutagenesis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structures of multiple complexes with functional validation; defines receptor assembly architecture\",\n      \"pmids\": [\"35863378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"NMR and X-ray crystallography of peptide–IL-17A complexes; SPR binding assays; cell-based IL-17A neutralization assay; structure-guided medicinal chemistry\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural determination combined with functional neutralization assays\",\n      \"pmids\": [\"27527709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; genetic knockouts; reporter assays for NF-κB and MAPK; mRNA stability assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — synthesizes multiple independent experimental studies; some findings from single labs\",\n      \"pmids\": [\"31316496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Primary human islet stimulation; RNA interference (STAT1 knockdown); STAT1 knockout mouse islets; RT-PCR; ELISA; nuclear dye viability assay\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNAi knockdown replicated in mouse genetic knockout; multiple readouts in primary human tissue\",\n      \"pmids\": [\"24352375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct kinase activation (phospho-Western) combined with functional differentiation assay; single laboratory\",\n      \"pmids\": [\"25557204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Digestive diseases and sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro dose-response with in vivo antibody blockade; single laboratory; moderate mechanistic depth\",\n      \"pmids\": [\"30097894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct biochemical interaction (Co-IP), site-specific PTM (deacetylation at K192), ChIP at promoter, and in vivo conditional KO phenotype\",\n      \"pmids\": [\"38135684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; competitive binding assays; FXYD3 conditional keratinocyte knockout; IMQ-induced psoriasis mouse model; NF-κB and MAPK signaling assays; cytokine/chemokine profiling\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with competitive binding mechanistic dissection + in vivo genetic model; multiple orthogonal approaches\",\n      \"pmids\": [\"36693922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multi-omic approach (scRNA-seq, ChIP-seq, RNA-seq) with functional readouts; chromatin-level mechanistic dissection\",\n      \"pmids\": [\"37244461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro synergy mechanistically confirmed; in vivo epistasis with IL-17A knockout validates requirement\",\n      \"pmids\": [\"28765647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout + antibody neutralization + cellular source identification; multiple in vivo readouts\",\n      \"pmids\": [\"27114524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-culture system with in vivo confirmation; indirect mechanism inferred rather than directly probed\",\n      \"pmids\": [\"32117261\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-17A is a disulfide-linked homodimer (cystine-knot fold) secreted by Th17 cells, γδ T cells, mast cells, and neutrophils that signals through an IL-17RA/IL-17RC heterodimer assembled in a 'tip-to-tip' architecture; the proximal adaptor Act1 (recruited via SEFIR–SEFIR domain interaction) engages TRAF proteins (especially TRAF6) to activate NF-κB, MAPK, and C/EBP pathways, inducing IL-6, IL-8, G-CSF, antimicrobial peptides, and CXC chemokines in stromal and epithelial cells; IκBζ and STAT1 serve as additional downstream transducers in specific cell types; IL-17A drives osteoclastogenesis indirectly through osteoblast RANKL/PGE2 upregulation, recruits neutrophils via CXC chemokine release from airway epithelium, inhibits adipogenesis and glucose uptake, promotes metabolic reprogramming of lymph node stromal cells through CPT1A induction, and acts directly on CNS neurons (via IL-17Ra) to modulate sociability, with its transcription regulated epigenetically by SIRT6-mediated RORγt deacetylation at K192 and by STAT5 signaling at the IL17A-F locus.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL-17A is a proinflammatory cytokine produced primarily by Th17 cells that orchestrates innate and adaptive immune responses by driving expression of chemokines, cytokines, and adhesion molecules in diverse target cells including fibroblasts, epithelial cells, and neurons. Structurally, IL-17A is a disulfide-linked homodimer with a cystine-knot fold that assembles a C2-symmetric ternary signaling complex with IL-17RA and IL-17RC through a tip-to-tip receptor architecture [PMID:19835883, PMID:35863378]. Upon receptor engagement, the SEFIR-domain adaptor Act1 recruits TRAF proteins to activate NF-κB, MAPK/ERK, and C/EBP cascades, driving proinflammatory gene expression; in fibroblastic reticular cells, this signaling induces the transcriptional co-activator IκBζ to reprogram glucose and fatty acid metabolism via CPT1A [PMID:18061473, PMID:24011563, PMID:30962593]. Transcription of the IL-17A gene is epigenetically regulated by SIRT6-mediated deacetylation of RORγt at K192, which promotes RORγt recruitment to the IL-17A promoter, while a positive-feedback loop through FXYD3 amplifies downstream signaling by competitively displacing the negative regulator TRAF3 from the IL-17R–Act1 complex [PMID:38135684, PMID:36693922].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Identification of IL-17A as a T-cell-derived secreted cytokine that induces proinflammatory mediators established the founding member of a new cytokine family distinct from known interleukin families.\",\n      \"evidence\": \"cDNA cloning from CD4+ T cell library with recombinant protein expression and cytokine ELISA on human fibroblasts\",\n      \"pmids\": [\"7499828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"receptor identity unknown\", \"signaling pathway not defined\", \"in vivo relevance not established\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that the adaptor Act1 connects IL-17R to downstream signaling via its SEFIR domain resolved how this structurally unique receptor family transduces signals, and showed Act1-deficient mice are resistant to Th17-driven autoimmunity.\",\n      \"evidence\": \"Act1 knockout mice, Co-IP domain mapping, EAE and colitis disease models\",\n      \"pmids\": [\"18061473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TRAF specificity downstream of Act1 not fully resolved\", \"SEFIR–SEFIR interaction structural basis unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Consolidation of the IL-17A signaling cascade through IL-17RA, Act1, NF-κB, MAPK, and C/EBP pathways established a canonical signaling framework and distinguished IL-17 receptor signaling from TLR and IL-1R SEFIR-independent pathways.\",\n      \"evidence\": \"Multiple signaling assays and genetic models synthesized across laboratories\",\n      \"pmids\": [\"19575028\", \"24011563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"relative contribution of individual TRAF family members unclear\", \"mRNA stabilization mechanism not fully defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Determination of the IL-17A homodimer crystal structure at 2.6 Å revealed the cystine-knot fold and dimeric architecture, providing the first atomic-level understanding of ligand organization and antibody epitope mapping.\",\n      \"evidence\": \"X-ray crystallography with H/D exchange mass spectrometry and mutagenesis\",\n      \"pmids\": [\"19835883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"receptor-bound conformation unknown at the time\", \"heterodimer (IL-17A/F) structure not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstration that IL-17A activates ERK1/2 within minutes in oligodendrocyte progenitor cells and promotes their differentiation extended IL-17A biology beyond classical inflammatory target cells to CNS progenitor cell fate decisions.\",\n      \"evidence\": \"Primary murine OPC culture with ERK phosphorylation kinetics and cerebellar slice culture differentiation assay\",\n      \"pmids\": [\"25557204\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ERK activation mechanism in OPCs not fully delineated\", \"in vivo relevance to remyelination not shown\", \"single lab finding\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Multiple studies placed IL-17A signaling through Act1/TRAF6/NF-κB in specific disease-relevant cell types—Müller cells in diabetic retinopathy, microglia in intracerebral hemorrhage, and synoviocytes in arthritis—demonstrating the conserved core pathway operates across diverse tissues with context-dependent outcomes.\",\n      \"evidence\": \"siRNA/inhibitor studies in Müller cells, neutralizing antibody in ICH mouse model, FLS stimulation with Il17a−/− mice in arthritis\",\n      \"pmids\": [\"27980343\", \"27107665\", \"28765647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"tissue-specific co-receptor usage not resolved\", \"relative contribution of MyD88 vs SEFIR-only signaling in microglia unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Structure-guided design of small-molecule macrocyclic IL-17A antagonists that block the receptor-binding surface validated the druggability of the IL-17A homodimer interface.\",\n      \"evidence\": \"Structural NMR/X-ray binding site mapping with cell-based neutralization assays\",\n      \"pmids\": [\"27527709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"in vivo efficacy of small molecules not demonstrated\", \"selectivity over IL-17A/F heterodimer not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"IL-17A signaling in fibroblastic reticular cells was shown to induce IκBζ-dependent metabolic reprogramming—increasing glucose uptake and CPT1A-mediated fatty acid oxidation—revealing that IL-17A controls stromal cell metabolism in addition to inflammatory gene expression.\",\n      \"evidence\": \"Genetic IL-17R knockout in FRCs, EAE/colitis models, metabolic flux assays\",\n      \"pmids\": [\"30962593\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"whether metabolic reprogramming occurs in other IL-17-responsive stromal cells unknown\", \"IκBζ target gene repertoire beyond CPT1A not fully catalogued\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Direct neuronal action of IL-17A via IL-17RA on somatosensory cortex neurons was shown to modulate social behavior, establishing a non-immune signaling role for IL-17A in brain circuit function.\",\n      \"evidence\": \"Intracranial IL-17A delivery, conditional IL-17RA knockout in S1DZ neurons, behavioral and electrophysiological recordings\",\n      \"pmids\": [\"31853066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"downstream neuronal signaling cascade not identified\", \"whether Act1/TRAF pathway operates in neurons not confirmed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Cryo-EM structures of binary IL-17A–IL-17RA and ternary IL-17A–IL-17RA–IL-17RC complexes revealed a C2-symmetric tip-to-tip receptor architecture, resolving how two receptor chains are organized around the homodimeric ligand to initiate signaling.\",\n      \"evidence\": \"Cryo-EM at near-atomic resolution, single-molecule imaging, cell-based signaling assays\",\n      \"pmids\": [\"35863378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"intracellular SEFIR domain arrangement in the activated complex not resolved\", \"heterodimer IL-17A/F ternary complex structure not determined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Two regulatory mechanisms governing IL-17A signaling amplitude and production were defined: SIRT6 deacetylates RORγt at K192 to enhance IL-17A transcription, while FXYD3 amplifies receptor-proximal signaling by competitively displacing TRAF3 from the IL-17R–Act1 complex.\",\n      \"evidence\": \"Conditional Sirt6 KO, ChIP at IL-17A promoter, Co-IP showing FXYD3–TRAF3 competition, keratinocyte-specific FXYD3 deletion in psoriasis model\",\n      \"pmids\": [\"38135684\", \"36693922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"whether SIRT6–RORγt axis operates in all Th17 subsets unknown\", \"FXYD3 mechanism not tested outside keratinocytes\", \"other post-translational modifications of RORγt affecting IL-17A locus not catalogued\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Differential epigenetic regulation of IL-17A versus IL-17F by STAT5/IL-2 signaling in psoriatic Th17 cells revealed that the two paralogs are governed by opposing chromatin states and expressed in largely distinct cell populations.\",\n      \"evidence\": \"Single-cell RNA-seq, cytokine-capture with ChIP-seq/RNA-seq, H3K4me3 analysis\",\n      \"pmids\": [\"37244461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"functional consequence of differential expression in vivo not tested\", \"whether this regulation applies beyond psoriatic Th17 cells unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions remain regarding the intracellular structural organization of the activated receptor complex (SEFIR domain arrangement), the full repertoire of tissue-specific co-receptors and their signaling consequences, the neuronal downstream signaling cascade, and the structural basis of IL-17A/F heterodimer receptor engagement.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"intracellular SEFIR–SEFIR complex structure not resolved\", \"neuronal IL-17RA signaling pathway components uncharacterized\", \"IL-17A/F heterodimer ternary complex structure not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 5, 7, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 5, 7, 13, 18]}\n    ],\n    \"complexes\": [\n      \"IL-17A homodimer\",\n      \"IL-17A–IL-17RA–IL-17RC ternary complex\"\n    ],\n    \"partners\": [\n      \"IL17RA\",\n      \"IL17RC\",\n      \"TRAF6IN1\",\n      \"TRAF3\",\n      \"FXYD3\",\n      \"SIRT6\",\n      \"RORC\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"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.\",\n      \"evidence\": \"cDNA subtraction cloning from activated murine T cell hybridoma; sequence analysis revealing 57% identity with HVS ORF13\",\n      \"pmids\": [\"8390535\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protein structure unknown\", \"Receptor unidentified\", \"Biological function of the secreted protein not yet determined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"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.\",\n      \"evidence\": \"Recombinant protein expression; cytokine ELISA on fibroblasts, epithelial and endothelial cells; CD34+ progenitor co-culture differentiation assays\",\n      \"pmids\": [\"7499828\", \"8676080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor identity unknown\", \"Signaling pathway not mapped\", \"In vivo relevance not yet tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"10225978\", \"9973514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor subunit composition still undefined\", \"Intracellular signaling cascade not yet identified\", \"Source T cell subset not characterized\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cytokine stimulation of murine memory T cells; IL-17A ELISA comparing IL-23 versus IL-12\",\n      \"pmids\": [\"12417590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Th17 lineage not yet formally defined\", \"Transcription factors controlling IL-17A expression unknown\", \"Role of TGF-β not yet established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"evidence\": \"Th17 differentiation assays; intracellular cytokine staining; keratinocyte stimulation with recombinant cytokines; RT-PCR for β-defensin 2, S100A7/A8/A9\",\n      \"pmids\": [\"16982811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor complex composition not yet resolved\", \"Relative contribution of IL-17A versus IL-17F in vivo unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Act1 knockout mice resistant to EAE and colitis; domain deletion mapping; co-immunoprecipitation with IL-17R\",\n      \"pmids\": [\"18061473\", \"19575028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TRAF specificity downstream of Act1 not fully dissected\", \"Role of IL-17RC as obligate co-receptor not yet structurally proven\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"X-ray crystallography of IL-17A–Fab complex; H/D exchange mass spectrometry; site-directed mutagenesis; cell-based neutralization\",\n      \"pmids\": [\"19835883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full receptor complex structure not yet determined\", \"IL-17A/F heterodimer structure unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"Immunohistochemistry of human psoriatic biopsies; Tcrd−/−, Tcra−/−, Il17ra−/− mice with IL-23 and imiquimod models; human genetic sequencing with functional receptor-ligand assays\",\n      \"pmids\": [\"21606249\", \"21982596\", \"21350122\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each cellular source across tissues not quantified\", \"Whether IL-17A and IL-17F are functionally redundant in antifungal defense remains unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"STAT1 RNAi in primary human islets; Stat1 knockout mouse islets; cytokine co-stimulation; ELISA and viability assays\",\n      \"pmids\": [\"24352375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STAT1 activation is direct or requires Act1/TRAF machinery is unclear\", \"Generalizability beyond pancreatic islets not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"NMR and X-ray crystallography of peptide–IL-17A complexes; SPR binding; cell-based neutralization\",\n      \"pmids\": [\"27527709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo pharmacokinetics and efficacy of macrocyclic antagonists not demonstrated\", \"Selectivity over IL-17A/F heterodimer not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"31853066\", \"30962593\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neuronal signaling intermediates downstream of IL-17Ra in cortex not identified\", \"Whether FRC metabolic reprogramming is conserved across all secondary lymphoid organs is unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cryo-EM; single-molecule imaging; structure–function mutagenesis; cell-based signaling assays\",\n      \"pmids\": [\"35863378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"38135684\", \"37244461\", \"36693922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoplasmic signaling complex structure unresolved\", \"IL-17A/F heterodimer receptor complex not structurally characterized\", \"Neuronal downstream signaling unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 2, 4, 8, 17, 18]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [9, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 2, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 4, 6, 7, 9, 11, 12, 13, 14, 19, 24, 27]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 9, 14, 17, 19, 24]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 10, 14, 20, 22]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"complexes\": [\n      \"IL-17A homodimer\",\n      \"IL-17A–IL-17RA–IL-17RC ternary signaling complex\"\n    ],\n    \"partners\": [\n      \"IL17RA\",\n      \"IL17RC\",\n      \"TRAF6IP2\",\n      \"TRAF6\",\n      \"TRAF3\",\n      \"IL22\",\n      \"FXYD3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}