{"gene":"IL17F","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2007,"finding":"IL-17A and IL-17F form not only homodimers but also a heterodimeric cytokine (IL-17A/F) when co-expressed; fully differentiated mouse Th17 cells naturally secrete all three forms. Recombinant IL-17A/F exhibits intermediate potency in inducing IL-6 and CXCL1 compared to homodimers. IL-17A/F regulation of IL-6 and CXCL1 is dependent on IL-17RA and TRAF6.","method":"Overexpression in 293T cells, recombinant protein assays in vitro, Th17 cell culture, siRNA/antibody blockade of IL-17RA and TRAF6","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (overexpression, recombinant protein, genetic knockdown), replicated across two independent papers (PMID:17452998 and PMID:18025225)","pmids":["17452998","18025225"],"is_preprint":false},{"year":2008,"finding":"The IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex. Surface plasmon resonance shows IL-17F binds IL-17RC with comparable affinity to IL-17A, but the three cytokines bind IL-17RA with different affinities. IL-17F activity is preferentially inhibited by soluble IL-17RC, whereas IL-17A activity is preferentially inhibited by soluble IL-17RA; combined soluble receptors are required to block IL-17F/IL-17A heterodimer.","method":"siRNA knockdown of IL-17RA and IL-17RC, neutralizing antibodies, surface plasmon resonance binding assays, soluble receptor blockade","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (siRNA, antibody neutralization, SPR biophysics) in one study, replicated conceptually by PMID:20231694","pmids":["18684971"],"is_preprint":false},{"year":2008,"finding":"IL-17F proinflammatory gene expression in vitro requires IL-17 receptor A (IL-17RA), TRAF6, and Act1. In vivo, IL-17F overexpression in lung epithelium caused lymphocyte/macrophage infiltration and mucus hyperplasia. IL-17F-deficient mice (but not IL-17-deficient mice) had defective airway neutrophilia after allergen challenge; IL-17F deficiency also resulted in reduced colitis caused by DSS, whereas IL-17 knockout mice developed more severe disease.","method":"IL-17F knockout mice, IL-17F transgenic lung overexpression, in vitro cytokine stimulation with genetic knockouts, allergen challenge model, DSS colitis model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function (KO mice), transgenic overexpression, multiple in vivo disease models with defined phenotypic readouts","pmids":["18411338"],"is_preprint":false},{"year":2010,"finding":"IL-17RC is absolutely required for IL-17A, IL-17F, and IL-17A/F signaling both in vitro and in vivo, as demonstrated using Il-17rc-deficient mice. IL-17RC does not pre-associate with IL-17RA on the cell surface; rather, IL-17A induces formation of an IL-17RC/IL-17RA complex. The SEFIR domain of IL-17RC is not required for complex formation but is essential for IL-17A signal transduction.","method":"Il-17rc-deficient mice, in vitro signaling assays, cell surface co-immunoprecipitation/complex formation assays, domain mutagenesis (SEFIR domain), EAE disease model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple in vitro and in vivo readouts, domain-level mechanistic dissection","pmids":["20231694"],"is_preprint":false},{"year":2006,"finding":"The IL-17F His161Arg (H161R) variant lacks the ability to activate the MAPK pathway, cytokine production, and chemokine production in bronchial epithelial cells unlike wild-type IL-17F. Furthermore, the H161R variant blocks induction of IL-8 expression by wild-type IL-17F, functioning as a natural IL-17F antagonist.","method":"Recombinant wild-type and H161R mutant IL-17F proteins, in vitro stimulation of bronchial epithelial cells, MAPK pathway assays, cytokine/chemokine ELISA","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with site-specific mutant protein, multiple functional readouts (MAPK, cytokine, chemokine), single lab","pmids":["16630936"],"is_preprint":false},{"year":2007,"finding":"THi (Th17) cell differentiation is accompanied by selective histone H3 acetylation and Lys-4 tri-methylation specifically at IL-17 and IL-17F gene promoters. TGF-β and IL-6 synergistically promoted histone acetylation on these promoters at early T cell activation. Multiple noncoding conserved sequences within the IL-17–IL-17F locus also showed lineage-specific histone H3 hyperacetylation in Th17 cells.","method":"Chromatin immunoprecipitation (ChIP) in Th17, Th1, and Th2 cells; cytokine stimulation (TGF-β + IL-6)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with functional cytokine stimulation, single lab, multiple histone marks examined","pmids":["17218320"],"is_preprint":false},{"year":2012,"finding":"A cis-regulatory element (CNS2) physically interacts with both Il17 and Il17f gene promoters and is sufficient for regulating their selective transcription in Th17 cells. Targeted deletion of CNS2 impaired RORγt-driven IL-17 expression and substantially decreased IL-17F production, associated with defective chromatin remodeling and reduced recruitment of histone-modifying enzymes p300 and JMJD3 to the locus.","method":"CNS2 targeted deletion in mice, chromosome conformation/physical interaction assay, ChIP for p300 and JMJD3, in vitro Th17 differentiation, EAE model","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic deletion of regulatory element, multiple mechanistic readouts (chromatin interactions, histone enzyme recruitment, cytokine production, in vivo disease model)","pmids":["22244845"],"is_preprint":false},{"year":2007,"finding":"IL-17F induces IP-10 (CXCL10) expression in bronchial epithelial cells through the Raf1-MEK1/2-ERK1/2-p90RSK-CREB signaling pathway. MEK inhibitors (PD98059, U0126), Raf1 kinase inhibitor, and dominant-negative Raf1 blocked IP-10 production. IL-17F phosphorylated p90RSK and CREB; siRNA knockdown of p90RSK or CREB inhibited IP-10 expression.","method":"Bronchial epithelial cell culture, pharmacological kinase inhibitors, dominant-negative Raf1 overexpression, siRNA knockdown of p90RSK and CREB, ELISA, RT-PCR","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (inhibitors, dominant-negative, siRNA), single lab","pmids":["17418381"],"is_preprint":false},{"year":2009,"finding":"IL-17F induces IL-11 expression in bronchial epithelial cells via the Raf1-MEK1/2-ERK1/2-MSK1-CREB signaling pathway. IL-17F phosphorylated MSK1; MEK inhibitors blocked MSK1 phosphorylation. siRNA knockdown of MSK1 inhibited CREB activation, and siRNAs targeting MSK1 and CREB blocked IL-11 expression. Co-stimulation with IL-4 and IL-13 augmented IL-17F-induced IL-11.","method":"Bronchial epithelial cell culture, MEK/Raf1 inhibitors, dominant-negative Raf1, siRNA knockdown of MSK1 and CREB, phosphorylation assays","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple inhibitors and siRNA knockdown, single lab, mechanistic pathway dissection","pmids":["19251839"],"is_preprint":false},{"year":2008,"finding":"IL-17F induces IL-8 production in normal human epidermal keratinocytes through activation of the ERK1/2 (MEK) pathway. Selective MEK inhibitors significantly inhibited IL-17F-induced IL-8 production. In mouse skin, intradermal IL-17F injection induced IL-8 mRNA and ERK1/2 phosphorylation, and caused marked dermal neutrophilia that was inhibited by anti-IL-8 antibody.","method":"Keratinocyte cell culture with recombinant IL-17F, MEK inhibitors, in vivo mouse skin injection, anti-IL-8 neutralizing antibody, RT-PCR, ELISA, histology","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo mechanistic experiments with inhibitors and neutralizing antibody, single lab","pmids":["18830271"],"is_preprint":false},{"year":2010,"finding":"IL-17F induces IL-6 production in normal human epidermal keratinocytes in a time-dependent manner, which is attenuated by a chimeric inhibitor blocking the IL-17 receptor. IL-17F-induced IL-6 was higher than that induced by TNF-α or IL-17A. In mouse skin, intradermal IL-17F injection increased IL-6 mRNA expression 3.2-fold.","method":"Keratinocyte cell culture with recombinant IL-17F, IL-17 receptor chimeric inhibitor, in vivo mouse skin injection, RT-PCR, ELISA","journal":"Archives of dermatological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor blockade confirms IL-17R dependence, in vitro and in vivo concordant findings, single lab","pmids":["20148256"],"is_preprint":false},{"year":2017,"finding":"IL-17F stimulation of human keratinocytes induces IκBζ expression at mRNA and protein levels via p38 MAPK and NF-κB signaling pathways. IκBζ silencing by siRNA revealed it is a key mediator of specific IL-17F-inducible psoriasis-associated genes including DEFB4/hBD2, S100A7, CCL20, IL-8, and CHI3L1.","method":"Keratinocyte culture with recombinant IL-17F, siRNA knockdown of IκBζ, pharmacological inhibition of p38 MAPK and NF-κB, RT-PCR, Western blot, ELISA","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple gene expression readouts, signaling inhibitors, single lab","pmids":["27576147"],"is_preprint":false},{"year":2018,"finding":"IL-17F (but not IL-17A) suppression protects against chemically induced colitis in mice. Il17f-/- CD45RBhi CD4+ T cells induced milder colitis in Rag2-/- mice accompanied by increased intestinal Treg cells and expansion of Clostridium cluster XIVa (Treg-inducing microbiota) due to decreased expression of antimicrobial proteins. Anti-IL-17F antibody (but not anti-IL-17A antibody) suppressed colitis development.","method":"Il17f-/- mice, DSS colitis model, adoptive T cell transfer into Rag2-/- mice, anti-IL-17F neutralizing antibody treatment, 16S rRNA microbiota analysis, antimicrobial protein expression assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, adoptive transfer, antibody neutralization, microbiota mechanistic link, multiple orthogonal approaches in one study","pmids":["29915298"],"is_preprint":false},{"year":2009,"finding":"IL-17A suppresses IL-17F production and secretion via IL-17RA signaling. In Il17a-/- mice, plasma IL-17F levels were elevated. Adding recombinant IL-17A to Il17a-/- splenocyte cultures reduced IL-17F mRNA and protein. This suppressive effect was absent in IL-17RA-deficient cells, demonstrating the IL-17RA requirement.","method":"Il17a-/- mice, plasma cytokine measurement (ELISA), ex vivo splenocyte culture with recombinant IL-17A, IL-17RA-deficient cells as controls, RT-PCR and ELISA for IL-17F","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with receptor-deficient cell controls, multiple readouts (mRNA and protein), single lab","pmids":["19542376"],"is_preprint":false},{"year":2020,"finding":"Crystal structure of the extracellular domain of human IL-17RC in complex with IL-17F reveals that IL-17RC forms a symmetrical 2:1 complex with IL-17F (two IL-17RC molecules per IL-17F homodimer), competing with IL-17RA for cytokine binding. Biophysical studies show IL-17A and IL-17A/F heterodimer also form 2:1 complexes with IL-17RC, suggesting IL-17RA-independent IL-17 signaling pathways.","method":"X-ray crystallography of IL-17RC extracellular domain:IL-17F complex, biophysical binding assays (SPR/ITC)","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional biophysical validation, provides direct structural mechanism for receptor engagement","pmids":["32187518"],"is_preprint":false},{"year":2017,"finding":"IL-17F signals specifically through IL-17RC on epithelial cells and can exacerbate lower airway inflammation independently of IL-17RA. In Il17ra-/- mice, IL-17F/IL-17RC axis signaling significantly worsened Aspergillus/Pseudomonas lower airway infection and allergic airway inflammation. By contrast, in upper respiratory S. aureus infection, the IL-17F/IL-17RC axis was protective.","method":"Il17ra-/-, Il17a-/-, Il17f-/- knockout mice, airway infection models (Aspergillus, Pseudomonas, S. aureus), allergic airway inflammation model, comparison of receptor/ligand knockout phenotypes","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic KO strains, multiple infection/inflammation models, clear pathway position established by comparing IL-17RA vs. IL-17RC dependence","pmids":["28813677"],"is_preprint":false},{"year":2011,"finding":"IL-17F deficiency significantly inhibits spontaneous intestinal tumorigenesis in the small intestine of ApcMin/+ mice. IL-17F ablation decreased IL-1β, Cox-2, and IL-17RC expression in tumors and reduced immune cell infiltration in lamina propria. IL-17A expression from CD4 T cells in lamina propria remained unchanged in the absence of IL-17F.","method":"IL-17F-deficient ApcMin/+ mice, tumor counting, immunohistochemistry, RT-PCR for IL-1β, Cox-2, IL-17RC","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in a defined tumor model, multiple molecular readouts, single lab","pmids":["21939640"],"is_preprint":false},{"year":2011,"finding":"MyD88-dependent TLR4 activation by LPS induces IL-17F production in mouse peritoneal macrophages, peaking at 12 h. C5a amplifies IL-17F production via C5aR through PI3K-Akt signaling (phosphorylation at Thr308 but not Ser473). Pharmacological inhibition of PI3K-Akt greatly reduced IL-17F production and mRNA. Full in vivo IL-17F production during endotoxemia and CLP sepsis requires C5a.","method":"MyD88-/- macrophages, LPS stimulation, recombinant C5a treatment, PI3K-Akt inhibitors, in vivo endotoxemia and CLP sepsis models, ELISA and RT-PCR","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO (MyD88-/-) combined with pharmacological inhibition and in vivo models, single lab","pmids":["21859896"],"is_preprint":false},{"year":2016,"finding":"IL-17F-deficient mice are protected from hepatocellular damage in a methionine-choline deficient diet (MCDD)-induced NAFLD model, similar to IL-17A-/- and IL-17RA-/- mice, despite increased steatosis. Protection correlated with decreased hepatic T-cell and macrophage infiltration and decreased expression of inflammatory mediators.","method":"IL-17F-/-, IL-17A-/-, IL-17RA-/- knockout mice fed MCDD, liver histology, flow cytometry of hepatic immune cells, inflammatory mediator expression","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in a defined disease model with multiple mechanistic readouts, single lab","pmids":["26895034"],"is_preprint":false},{"year":2016,"finding":"IL-17F drives renal tissue injury in acute crescentic GN (nephrotoxic nephritis) through CD4+ T cell-derived IL-17F promoting neutrophil recruitment via induction of CXCL1 and CXCL5 in kidney cells. IL-17F-deficient nephritic mice had fewer renal infiltrating neutrophils; neutrophil depletion did not further affect GN in IL-17F-deficient mice. In chronic SLE (pristane) model, IL-17F-deficient mice developed less severe disease.","method":"IL-17F-/- mice, nephrotoxic nephritis model, IL-17F-neutralizing antibodies, adoptive transfer into Rag1-/- mice, neutrophil depletion, pristane-induced SLE model, CXCL1/CXCL5 induction assay in kidney cells","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, antibody neutralization, adoptive transfer, and cell depletion experiments with consistent mechanistic conclusions across multiple models","pmids":["27030744"],"is_preprint":false},{"year":2023,"finding":"IL-17A and IL-17F are differentially regulated in psoriatic disease: their expression predominantly occurs in distinct T cell populations. STAT5/IL-2 signaling has opposing effects on each gene. Higher IL-17F expression is linked to greater cell proliferation. The IL17A-F locus carries a broad H3K4me3 region reflecting epigenetic plasticity.","method":"Single-cell RNA sequencing, novel cytokine-capture technique combined with ChIP-seq and RNA-seq, lesional skin tissue from psoriasis patients, in vitro culture systems with methylprednisolone treatment","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal genomic and functional methods, patient tissue plus in vitro, single lab","pmids":["37244461"],"is_preprint":false},{"year":2013,"finding":"PGE2 and IL-23 plus IL-1β differentially regulate IL-17A and IL-17F in human Th17 memory cells: PGE2 induces IL-17A but not IL-17F via the EP4 receptor, promoting a switch from IL-17F to IL-17A predominant responses. IL-23 plus IL-1β preferentially induce IL-17F. The IL17A and IL17F loci have divergent epigenetic architectures in Th17 cells, with IL17A poised for preferential expression.","method":"Activated human peripheral CD4+ memory T cells and sorted Th17 memory cells, gene expression profiling, ChIP for histone marks, pharmacological EP4 receptor studies","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human primary cells with pharmacological and epigenetic mechanistic dissection, single lab","pmids":["23800789"],"is_preprint":false},{"year":2019,"finding":"Fusobacterium nucleatum promotes intestinal inflammation in UC by targeting CARD3 through NOD2, which activates the IL-17F/NF-κB pathway in intestinal epithelial cells in vitro and in vivo.","method":"F. nucleatum infection of UC cell lines and mouse models in vivo, CARD3 knockdown/overexpression, NF-κB pathway reporters, IL-17F cytokine measurement by ELISA","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic in vitro and in vivo pathway dissection, single lab","pmids":["31610014"],"is_preprint":false},{"year":2015,"finding":"IL-17A and IL-17F are both required for antimicrobial peptide production (mBD-3, CRAMP, mBD-14) and clearance of S. aureus nasal colonization in mice. Mice deficient in both IL-17A and IL-17F lost the ability to clear S. aureus; IL-17A alone was sufficient for nasal mBD-3 production ex vivo.","method":"IL-17A/IL-17F double-deficient mice, S. aureus nasal colonization model, ex vivo nasal tissue supernatant antimicrobial activity assay, antimicrobial peptide expression (RT-PCR, ELISA)","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined antimicrobial peptide mechanistic readout, single lab","pmids":["27736775"],"is_preprint":false},{"year":2019,"finding":"In a TDI-induced steroid-insensitive asthma model, anti-IL-17F (but not anti-IL-17A) treatment ameliorated airway hyperresponsiveness and bronchial neutrophilia with decreased Th17 responses, while anti-IL-17A increased AHR and eosinophilia with amplified Th2 responses. Recombinant IL-17A and IL-17F showed opposite effects consistent with the antibody results, demonstrating distinct and opposing biological roles in this context.","method":"TDI-sensitized BALB/c mice, anti-IL-17A and anti-IL-17F monoclonal antibody treatment, recombinant IL-17A and IL-17F administration, airway hyperresponsiveness measurement, bronchoalveolar lavage cell counts, cytokine profiling","journal":"The European respiratory journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo antibody neutralization and recombinant protein rescue, mechanistic dissection of distinct roles, single lab","pmids":["30655284"],"is_preprint":false},{"year":2020,"finding":"IL-17A and IL-17F enhance in vitro osteogenic differentiation and bone formation from human periosteal-derived cells (hPDCs). Dual neutralization of IL-17A and IL-17F by bimekizumab blocked T cell supernatant-induced and patient AS serum-induced in vitro bone formation more deeply than neutralization of either cytokine alone. Osteogenic blockade may involve increased expression of the Wnt antagonist DKK1.","method":"Human periosteal-derived cell osteogenic differentiation assay, recombinant IL-17A and IL-17F, T cell supernatants, AS patient serum, bimekizumab and monospecific antibody treatment, DKK1 expression assay","journal":"RMD open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro biomimetic model with recombinant proteins and patient samples, mechanistic DKK1 link, single lab","pmids":["32723833"],"is_preprint":false},{"year":2015,"finding":"IL-17A and IL-17F induce autophagy in RAW 264.7 macrophages, as shown by LC3B-II accumulation, enhanced autophagic flux, increased autophagosome number/size, and acidic vesicular organelle formation. IL-17F was more efficient than IL-17A in promoting autophagy. IL-17F treatment significantly decreased intracellular counts of Mycobacterium terrae in macrophages.","method":"RAW 264.7 macrophage culture, recombinant IL-17A and IL-17F, LC3B-II Western blot, confocal microscopy of autophagosome formation, autophagic flux assay, intracellular M. terrae colony-forming unit counting","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal autophagy assays with functional bacterial clearance readout, single lab","pmids":["26796276"],"is_preprint":false}],"current_model":"IL-17F is a disulfide-linked homodimeric cytokine (and component of an IL-17A/F heterodimer) produced predominantly by Th17 cells that signals through the IL-17RA/IL-17RC receptor heterodimer—with IL-17RC forming a 2:1 complex with IL-17F as revealed by crystal structure—requiring the adaptors Act1 and TRAF6 to activate NF-κB and MAPK (Raf1-MEK-ERK-p90RSK-CREB) cascades in epithelial and stromal cells, inducing proinflammatory chemokines (CXCL1, CXCL5, IL-8/CXCL8, IP-10/CXCL10, CCL20), cytokines (IL-6, IL-11), and antimicrobial peptides; its expression at the IL17A–IL17F locus is controlled by a lineage-specific cis-regulatory element (CNS2) that recruits p300 and JMJD3 and is epigenetically marked by H3K4me3 and H3K27 acetylation in Th17 cells, with STAT5/IL-2 signaling differentially regulating IL-17F versus IL-17A; in vivo, IL-17F plays non-redundant roles distinct from IL-17A in driving neutrophilic airway inflammation, colitis (partly via regulation of intestinal microbiota and Treg induction), crescentic glomerulonephritis, and osteogenic differentiation, and a natural loss-of-function variant (H161R) acts as an endogenous IL-17F antagonist."},"narrative":{"mechanistic_narrative":"IL-17F is a proinflammatory cytokine produced by Th17 cells that drives neutrophilic tissue inflammation and antimicrobial defense through a dedicated IL-17 receptor signaling axis [PMID:18411338, PMID:28813677]. It exists as a disulfide-linked homodimer and also pairs with IL-17A to form an IL-17A/F heterodimer, all of which are secreted by differentiated Th17 cells [PMID:17452998, PMID:18025225]. IL-17F signals through the IL-17RA/IL-17RC receptor heterodimer—binding IL-17RC with affinity comparable to IL-17A while engaging IL-17RA distinctly—and a crystal structure of the IL-17RC extracellular domain bound to IL-17F shows a symmetrical 2:1 IL-17RC:cytokine complex that competes with IL-17RA, defining a basis for IL-17RA-independent signaling [PMID:18684971, PMID:32187518]. IL-17F-induced gene expression requires IL-17RA, IL-17RC, the adaptor Act1, and TRAF6, and IL-17RC is induced into complex with IL-17RA rather than pre-associated [PMID:18411338, PMID:20231694]. Downstream, IL-17F activates the Raf1-MEK-ERK-p90RSK/MSK1-CREB cascade and NF-κB/IκBζ-dependent transcription in epithelial and stromal cells to induce chemokines (CXCL10/IP-10, IL-8, CXCL1, CXCL5, CCL20), cytokines (IL-6, IL-11), and antimicrobial peptides (DEFB4, S100A7) [PMID:17418381, PMID:19251839, PMID:27576147, PMID:27030744]. In vivo, IL-17F plays roles distinct from and sometimes opposing IL-17A, driving allergic and infection-associated airway neutrophilia, DSS colitis (via regulation of the intestinal microbiota and Treg balance), and crescentic glomerulonephritis through CXCL1/CXCL5-mediated neutrophil recruitment [PMID:18411338, PMID:29915298, PMID:27030744, PMID:30655284]. Its expression at the shared IL17A–IL17F locus is governed by a Th17-lineage cis-regulatory element (CNS2) that recruits p300 and JMJD3 and bears H3K4me3/H3K27 acetylation marks, with STAT5/IL-2 and prostaglandin/cytokine inputs differentially partitioning IL-17F versus IL-17A output [PMID:17218320, PMID:22244845, PMID:23800789]. A natural His161Arg variant is signaling-dead and dominantly blocks wild-type IL-17F, acting as an endogenous antagonist [PMID:16630936].","teleology":[{"year":2006,"claim":"Established that IL-17F is a functional epithelial-activating cytokine and identified a natural loss-of-function variant, revealing both its signaling output and a mechanism of endogenous antagonism.","evidence":"Recombinant wild-type and H161R IL-17F on bronchial epithelial cells with MAPK and cytokine/chemokine readouts","pmids":["16630936"],"confidence":"High","gaps":["Did not define the receptor or adaptor requirements","Structural basis of H161R antagonism not resolved"]},{"year":2007,"claim":"Defined the proximal MAPK signaling route by which IL-17F drives chemokine output, establishing the Raf1-MEK-ERK-p90RSK-CREB cascade.","evidence":"Kinase inhibitors, dominant-negative Raf1, and siRNA of p90RSK/CREB in bronchial epithelial cells measuring IP-10","pmids":["17418381"],"confidence":"Medium","gaps":["Receptor engagement upstream of Raf1 not addressed","Single cell type"]},{"year":2007,"claim":"Showed that IL-17A and IL-17F form a heterodimer in addition to homodimers and are co-secreted by Th17 cells, and that IL-17F locus activation is epigenetically programmed during Th17 differentiation.","evidence":"Overexpression/recombinant protein assays plus ChIP for histone marks at the IL-17/IL-17F locus in Th17 cells","pmids":["17452998","18025225","17218320"],"confidence":"High","gaps":["Receptor specificity of the heterodimer not yet defined","Regulatory element driving locus marks not identified"]},{"year":2008,"claim":"Identified the receptor and adaptor requirements for IL-17F signaling and demonstrated non-redundant in vivo roles distinct from IL-17A in airway and intestinal inflammation.","evidence":"IL-17F knockout and transgenic mice, genetic knockouts of IL-17RA/TRAF6/Act1 in vitro, SPR binding, and allergen/DSS colitis models","pmids":["18411338","18684971"],"confidence":"High","gaps":["Stoichiometry of receptor binding unresolved","Mechanism of opposing IL-17A vs IL-17F colitis phenotypes unclear"]},{"year":2009,"claim":"Extended the MAPK signaling model to IL-11 induction and showed reciprocal regulation in which IL-17A suppresses IL-17F production through IL-17RA.","evidence":"MSK1/CREB siRNA and inhibitors in epithelial cells; Il17a-/- mice and IL-17RA-deficient cells measuring IL-17F","pmids":["19251839","19542376"],"confidence":"Medium","gaps":["Molecular basis of IL-17A-mediated feedback on IL-17F transcription not defined"]},{"year":2010,"claim":"Established IL-17RC as absolutely required for IL-17F signaling and showed the receptor complex is ligand-induced rather than pre-formed, with the SEFIR domain essential for transduction but not assembly.","evidence":"Il17rc-/- mice, cell-surface complex-formation assays, and SEFIR domain mutagenesis","pmids":["20231694"],"confidence":"High","gaps":["Quantitative receptor stoichiometry not resolved at this stage"]},{"year":2012,"claim":"Identified the CNS2 cis-regulatory element as the locus-control mechanism that physically contacts the Il17/Il17f promoters and recruits histone-modifying enzymes to enable selective Th17 transcription.","evidence":"CNS2 targeted deletion in mice with chromosome-conformation assays and ChIP for p300 and JMJD3","pmids":["22244845"],"confidence":"High","gaps":["How CNS2 differentially partitions IL-17F vs IL-17A output not fully defined"]},{"year":2016,"claim":"Resolved the mechanism of IL-17F-driven tissue injury in glomerulonephritis as CXCL1/CXCL5-mediated neutrophil recruitment, and demonstrated requirement in NAFLD inflammation.","evidence":"Il17f-/- mice, neutralizing antibodies, adoptive transfer, neutrophil depletion in nephritis models; MCDD diet model","pmids":["27030744","26895034"],"confidence":"High","gaps":["Cell-type-specific source of pathogenic IL-17F in chronic models not fully dissected"]},{"year":2017,"claim":"Defined an IL-17RA-independent IL-17F/IL-17RC signaling axis on epithelium with context-dependent protective vs pathogenic outcomes, and identified IκBζ as a transcriptional mediator of psoriasis-associated genes.","evidence":"Il17ra-/-/Il17a-/-/Il17f-/- mice in airway infection/inflammation models; IκBζ siRNA and p38/NF-κB inhibitors in keratinocytes","pmids":["28813677","27576147"],"confidence":"High","gaps":["Structural basis of IL-17RA-independent signaling not yet shown","Determinants of protective vs pathogenic outcome unclear"]},{"year":2018,"claim":"Showed IL-17F shapes the intestinal microbiota and Treg balance, providing a mechanistic basis for its selective pathogenicity in colitis distinct from IL-17A.","evidence":"Il17f-/- mice, adoptive transfer into Rag2-/-, anti-IL-17F antibody, and 16S microbiota analysis","pmids":["29915298"],"confidence":"High","gaps":["Direct antimicrobial-protein targets mediating microbiota shifts not enumerated"]},{"year":2020,"claim":"Provided the structural mechanism of receptor engagement, showing IL-17RC forms a symmetric 2:1 complex with IL-17F that competes with IL-17RA, rationalizing IL-17RA-independent signaling.","evidence":"X-ray crystallography of IL-17RC ectodomain:IL-17F complex with SPR/ITC biophysics","pmids":["32187518"],"confidence":"High","gaps":["How the 2:1 complex transduces signal in the absence of IL-17RA not resolved","No structure of the full signaling complex"]},{"year":2023,"claim":"Refined the picture of differential IL-17A vs IL-17F regulation in human disease, linking distinct T cell populations, STAT5/IL-2 signaling, and locus epigenetic architecture to selective IL-17F output.","evidence":"Single-cell RNA-seq, cytokine-capture with ChIP-seq/RNA-seq on psoriatic skin and in vitro culture","pmids":["37244461"],"confidence":"Medium","gaps":["Causal regulators distinguishing the two genes not fully isolated","Single-lab dataset"]},{"year":null,"claim":"How the IL-17F/IL-17RC 2:1 complex transduces signal independently of IL-17RA, and what determines whether IL-17F output is protective versus pathogenic in a given tissue, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of an IL-17RA-independent signaling-competent complex","Tissue-context switch between protective and pathogenic IL-17F responses unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,4,7,9,10,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,13]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,12,19,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,7,11,14]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,6,11,21]}],"complexes":[],"partners":["IL17RC","IL17RA","IL17A","TRAF6","ACT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96PD4","full_name":"Interleukin-17F","aliases":["Cytokine ML-1"],"length_aa":163,"mass_kda":18.0,"function":"Effector cytokine of innate and adaptive immune system involved in antimicrobial host defense and maintenance of tissue integrity (PubMed:21350122). IL17A-IL17F signals via IL17RA-IL17RC heterodimeric receptor complex, triggering homotypic interaction of IL17RA and IL17RC chains with TRAF3IP2 adapter through SEFIR domains. 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:11574464, PubMed:11591732, PubMed:11591768, PubMed:17911633, PubMed:18684971, PubMed:21350122, PubMed:28827714). IL17A-IL17F is primarily involved in host defense against extracellular bacteria and fungi by inducing neutrophilic inflammation (By similarity). As signature effector cytokine of T-helper 17 cells (Th17), primarily induces neutrophil activation and recruitment at infection and inflammatory sites (By similarity). Stimulates 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). IL17F homodimer can signal via IL17RC homodimeric receptor complex, triggering downstream activation of TRAF6 and NF-kappa-B signaling pathway (PubMed:32187518). Via IL17RC induces transcriptional activation of IL33, a potent cytokine that stimulates group 2 innate lymphoid cells and adaptive T-helper 2 cells involved in pulmonary allergic response to fungi. Likely via IL17RC, promotes sympathetic innervation of peripheral organs by coordinating the communication between gamma-delta T cells and parenchymal cells. Stimulates sympathetic innervation of thermogenic adipose tissue by driving TGFB1 expression (By similarity). Regulates the composition of intestinal microbiota and immune tolerance by inducing antimicrobial proteins that specifically control the growth of commensal Firmicutes and Bacteroidetes (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q96PD4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL17F","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL17F","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":"615207","title":"IMMUNODEFICIENCY 56; IMD56","url":"https://www.omim.org/entry/615207"},{"mim_id":"614995","title":"INTERLEUKIN 17 RECEPTOR E; IL17RE","url":"https://www.omim.org/entry/614995"},{"mim_id":"614162","title":"IMMUNODEFICIENCY 31C; IMD31C","url":"https://www.omim.org/entry/614162"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":2.0}],"url":"https://www.proteinatlas.org/search/IL17F"},"hgnc":{"alias_symbol":["IL-17F","ML-1","ML1"],"prev_symbol":[]},"alphafold":{"accession":"Q96PD4","domains":[{"cath_id":"2.10.90.10","chopping":"73-154","consensus_level":"high","plddt":97.7384,"start":73,"end":154}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96PD4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96PD4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96PD4-F1-predicted_aligned_error_v6.png","plddt_mean":87.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL17F","jax_strain_url":"https://www.jax.org/strain/search?query=IL17F"},"sequence":{"accession":"Q96PD4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96PD4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96PD4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96PD4"}},"corpus_meta":[{"pmid":"18411338","id":"PMC_18411338","title":"Regulation of inflammatory 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Recombinant IL-17A/F exhibits intermediate potency in inducing IL-6 and CXCL1 compared to homodimers. IL-17A/F regulation of IL-6 and CXCL1 is dependent on IL-17RA and TRAF6.\",\n      \"method\": \"Overexpression in 293T cells, recombinant protein assays in vitro, Th17 cell culture, siRNA/antibody blockade of IL-17RA and TRAF6\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (overexpression, recombinant protein, genetic knockdown), replicated across two independent papers (PMID:17452998 and PMID:18025225)\",\n      \"pmids\": [\"17452998\", \"18025225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex. Surface plasmon resonance shows IL-17F binds IL-17RC with comparable affinity to IL-17A, but the three cytokines bind IL-17RA with different affinities. IL-17F activity is preferentially inhibited by soluble IL-17RC, whereas IL-17A activity is preferentially inhibited by soluble IL-17RA; combined soluble receptors are required to block IL-17F/IL-17A heterodimer.\",\n      \"method\": \"siRNA knockdown of IL-17RA and IL-17RC, neutralizing antibodies, surface plasmon resonance binding assays, soluble receptor blockade\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (siRNA, antibody neutralization, SPR biophysics) in one study, replicated conceptually by PMID:20231694\",\n      \"pmids\": [\"18684971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-17F proinflammatory gene expression in vitro requires IL-17 receptor A (IL-17RA), TRAF6, and Act1. In vivo, IL-17F overexpression in lung epithelium caused lymphocyte/macrophage infiltration and mucus hyperplasia. IL-17F-deficient mice (but not IL-17-deficient mice) had defective airway neutrophilia after allergen challenge; IL-17F deficiency also resulted in reduced colitis caused by DSS, whereas IL-17 knockout mice developed more severe disease.\",\n      \"method\": \"IL-17F knockout mice, IL-17F transgenic lung overexpression, in vitro cytokine stimulation with genetic knockouts, allergen challenge model, DSS colitis model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function (KO mice), transgenic overexpression, multiple in vivo disease models with defined phenotypic readouts\",\n      \"pmids\": [\"18411338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-17RC is absolutely required for IL-17A, IL-17F, and IL-17A/F signaling both in vitro and in vivo, as demonstrated using Il-17rc-deficient mice. IL-17RC does not pre-associate with IL-17RA on the cell surface; rather, IL-17A induces formation of an IL-17RC/IL-17RA complex. The SEFIR domain of IL-17RC is not required for complex formation but is essential for IL-17A signal transduction.\",\n      \"method\": \"Il-17rc-deficient mice, in vitro signaling assays, cell surface co-immunoprecipitation/complex formation assays, domain mutagenesis (SEFIR domain), EAE disease model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple in vitro and in vivo readouts, domain-level mechanistic dissection\",\n      \"pmids\": [\"20231694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The IL-17F His161Arg (H161R) variant lacks the ability to activate the MAPK pathway, cytokine production, and chemokine production in bronchial epithelial cells unlike wild-type IL-17F. Furthermore, the H161R variant blocks induction of IL-8 expression by wild-type IL-17F, functioning as a natural IL-17F antagonist.\",\n      \"method\": \"Recombinant wild-type and H161R mutant IL-17F proteins, in vitro stimulation of bronchial epithelial cells, MAPK pathway assays, cytokine/chemokine ELISA\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with site-specific mutant protein, multiple functional readouts (MAPK, cytokine, chemokine), single lab\",\n      \"pmids\": [\"16630936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"THi (Th17) cell differentiation is accompanied by selective histone H3 acetylation and Lys-4 tri-methylation specifically at IL-17 and IL-17F gene promoters. TGF-β and IL-6 synergistically promoted histone acetylation on these promoters at early T cell activation. Multiple noncoding conserved sequences within the IL-17–IL-17F locus also showed lineage-specific histone H3 hyperacetylation in Th17 cells.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) in Th17, Th1, and Th2 cells; cytokine stimulation (TGF-β + IL-6)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with functional cytokine stimulation, single lab, multiple histone marks examined\",\n      \"pmids\": [\"17218320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A cis-regulatory element (CNS2) physically interacts with both Il17 and Il17f gene promoters and is sufficient for regulating their selective transcription in Th17 cells. Targeted deletion of CNS2 impaired RORγt-driven IL-17 expression and substantially decreased IL-17F production, associated with defective chromatin remodeling and reduced recruitment of histone-modifying enzymes p300 and JMJD3 to the locus.\",\n      \"method\": \"CNS2 targeted deletion in mice, chromosome conformation/physical interaction assay, ChIP for p300 and JMJD3, in vitro Th17 differentiation, EAE model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic deletion of regulatory element, multiple mechanistic readouts (chromatin interactions, histone enzyme recruitment, cytokine production, in vivo disease model)\",\n      \"pmids\": [\"22244845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IL-17F induces IP-10 (CXCL10) expression in bronchial epithelial cells through the Raf1-MEK1/2-ERK1/2-p90RSK-CREB signaling pathway. MEK inhibitors (PD98059, U0126), Raf1 kinase inhibitor, and dominant-negative Raf1 blocked IP-10 production. IL-17F phosphorylated p90RSK and CREB; siRNA knockdown of p90RSK or CREB inhibited IP-10 expression.\",\n      \"method\": \"Bronchial epithelial cell culture, pharmacological kinase inhibitors, dominant-negative Raf1 overexpression, siRNA knockdown of p90RSK and CREB, ELISA, RT-PCR\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (inhibitors, dominant-negative, siRNA), single lab\",\n      \"pmids\": [\"17418381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-17F induces IL-11 expression in bronchial epithelial cells via the Raf1-MEK1/2-ERK1/2-MSK1-CREB signaling pathway. IL-17F phosphorylated MSK1; MEK inhibitors blocked MSK1 phosphorylation. siRNA knockdown of MSK1 inhibited CREB activation, and siRNAs targeting MSK1 and CREB blocked IL-11 expression. Co-stimulation with IL-4 and IL-13 augmented IL-17F-induced IL-11.\",\n      \"method\": \"Bronchial epithelial cell culture, MEK/Raf1 inhibitors, dominant-negative Raf1, siRNA knockdown of MSK1 and CREB, phosphorylation assays\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple inhibitors and siRNA knockdown, single lab, mechanistic pathway dissection\",\n      \"pmids\": [\"19251839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-17F induces IL-8 production in normal human epidermal keratinocytes through activation of the ERK1/2 (MEK) pathway. Selective MEK inhibitors significantly inhibited IL-17F-induced IL-8 production. In mouse skin, intradermal IL-17F injection induced IL-8 mRNA and ERK1/2 phosphorylation, and caused marked dermal neutrophilia that was inhibited by anti-IL-8 antibody.\",\n      \"method\": \"Keratinocyte cell culture with recombinant IL-17F, MEK inhibitors, in vivo mouse skin injection, anti-IL-8 neutralizing antibody, RT-PCR, ELISA, histology\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo mechanistic experiments with inhibitors and neutralizing antibody, single lab\",\n      \"pmids\": [\"18830271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-17F induces IL-6 production in normal human epidermal keratinocytes in a time-dependent manner, which is attenuated by a chimeric inhibitor blocking the IL-17 receptor. IL-17F-induced IL-6 was higher than that induced by TNF-α or IL-17A. In mouse skin, intradermal IL-17F injection increased IL-6 mRNA expression 3.2-fold.\",\n      \"method\": \"Keratinocyte cell culture with recombinant IL-17F, IL-17 receptor chimeric inhibitor, in vivo mouse skin injection, RT-PCR, ELISA\",\n      \"journal\": \"Archives of dermatological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor blockade confirms IL-17R dependence, in vitro and in vivo concordant findings, single lab\",\n      \"pmids\": [\"20148256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-17F stimulation of human keratinocytes induces IκBζ expression at mRNA and protein levels via p38 MAPK and NF-κB signaling pathways. IκBζ silencing by siRNA revealed it is a key mediator of specific IL-17F-inducible psoriasis-associated genes including DEFB4/hBD2, S100A7, CCL20, IL-8, and CHI3L1.\",\n      \"method\": \"Keratinocyte culture with recombinant IL-17F, siRNA knockdown of IκBζ, pharmacological inhibition of p38 MAPK and NF-κB, RT-PCR, Western blot, ELISA\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple gene expression readouts, signaling inhibitors, single lab\",\n      \"pmids\": [\"27576147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-17F (but not IL-17A) suppression protects against chemically induced colitis in mice. Il17f-/- CD45RBhi CD4+ T cells induced milder colitis in Rag2-/- mice accompanied by increased intestinal Treg cells and expansion of Clostridium cluster XIVa (Treg-inducing microbiota) due to decreased expression of antimicrobial proteins. Anti-IL-17F antibody (but not anti-IL-17A antibody) suppressed colitis development.\",\n      \"method\": \"Il17f-/- mice, DSS colitis model, adoptive T cell transfer into Rag2-/- mice, anti-IL-17F neutralizing antibody treatment, 16S rRNA microbiota analysis, antimicrobial protein expression assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, adoptive transfer, antibody neutralization, microbiota mechanistic link, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"29915298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-17A suppresses IL-17F production and secretion via IL-17RA signaling. In Il17a-/- mice, plasma IL-17F levels were elevated. Adding recombinant IL-17A to Il17a-/- splenocyte cultures reduced IL-17F mRNA and protein. This suppressive effect was absent in IL-17RA-deficient cells, demonstrating the IL-17RA requirement.\",\n      \"method\": \"Il17a-/- mice, plasma cytokine measurement (ELISA), ex vivo splenocyte culture with recombinant IL-17A, IL-17RA-deficient cells as controls, RT-PCR and ELISA for IL-17F\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with receptor-deficient cell controls, multiple readouts (mRNA and protein), single lab\",\n      \"pmids\": [\"19542376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of the extracellular domain of human IL-17RC in complex with IL-17F reveals that IL-17RC forms a symmetrical 2:1 complex with IL-17F (two IL-17RC molecules per IL-17F homodimer), competing with IL-17RA for cytokine binding. Biophysical studies show IL-17A and IL-17A/F heterodimer also form 2:1 complexes with IL-17RC, suggesting IL-17RA-independent IL-17 signaling pathways.\",\n      \"method\": \"X-ray crystallography of IL-17RC extracellular domain:IL-17F complex, biophysical binding assays (SPR/ITC)\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional biophysical validation, provides direct structural mechanism for receptor engagement\",\n      \"pmids\": [\"32187518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-17F signals specifically through IL-17RC on epithelial cells and can exacerbate lower airway inflammation independently of IL-17RA. In Il17ra-/- mice, IL-17F/IL-17RC axis signaling significantly worsened Aspergillus/Pseudomonas lower airway infection and allergic airway inflammation. By contrast, in upper respiratory S. aureus infection, the IL-17F/IL-17RC axis was protective.\",\n      \"method\": \"Il17ra-/-, Il17a-/-, Il17f-/- knockout mice, airway infection models (Aspergillus, Pseudomonas, S. aureus), allergic airway inflammation model, comparison of receptor/ligand knockout phenotypes\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic KO strains, multiple infection/inflammation models, clear pathway position established by comparing IL-17RA vs. IL-17RC dependence\",\n      \"pmids\": [\"28813677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-17F deficiency significantly inhibits spontaneous intestinal tumorigenesis in the small intestine of ApcMin/+ mice. IL-17F ablation decreased IL-1β, Cox-2, and IL-17RC expression in tumors and reduced immune cell infiltration in lamina propria. IL-17A expression from CD4 T cells in lamina propria remained unchanged in the absence of IL-17F.\",\n      \"method\": \"IL-17F-deficient ApcMin/+ mice, tumor counting, immunohistochemistry, RT-PCR for IL-1β, Cox-2, IL-17RC\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in a defined tumor model, multiple molecular readouts, single lab\",\n      \"pmids\": [\"21939640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MyD88-dependent TLR4 activation by LPS induces IL-17F production in mouse peritoneal macrophages, peaking at 12 h. C5a amplifies IL-17F production via C5aR through PI3K-Akt signaling (phosphorylation at Thr308 but not Ser473). Pharmacological inhibition of PI3K-Akt greatly reduced IL-17F production and mRNA. Full in vivo IL-17F production during endotoxemia and CLP sepsis requires C5a.\",\n      \"method\": \"MyD88-/- macrophages, LPS stimulation, recombinant C5a treatment, PI3K-Akt inhibitors, in vivo endotoxemia and CLP sepsis models, ELISA and RT-PCR\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO (MyD88-/-) combined with pharmacological inhibition and in vivo models, single lab\",\n      \"pmids\": [\"21859896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-17F-deficient mice are protected from hepatocellular damage in a methionine-choline deficient diet (MCDD)-induced NAFLD model, similar to IL-17A-/- and IL-17RA-/- mice, despite increased steatosis. Protection correlated with decreased hepatic T-cell and macrophage infiltration and decreased expression of inflammatory mediators.\",\n      \"method\": \"IL-17F-/-, IL-17A-/-, IL-17RA-/- knockout mice fed MCDD, liver histology, flow cytometry of hepatic immune cells, inflammatory mediator expression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in a defined disease model with multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"26895034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-17F drives renal tissue injury in acute crescentic GN (nephrotoxic nephritis) through CD4+ T cell-derived IL-17F promoting neutrophil recruitment via induction of CXCL1 and CXCL5 in kidney cells. IL-17F-deficient nephritic mice had fewer renal infiltrating neutrophils; neutrophil depletion did not further affect GN in IL-17F-deficient mice. In chronic SLE (pristane) model, IL-17F-deficient mice developed less severe disease.\",\n      \"method\": \"IL-17F-/- mice, nephrotoxic nephritis model, IL-17F-neutralizing antibodies, adoptive transfer into Rag1-/- mice, neutrophil depletion, pristane-induced SLE model, CXCL1/CXCL5 induction assay in kidney cells\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, antibody neutralization, adoptive transfer, and cell depletion experiments with consistent mechanistic conclusions across multiple models\",\n      \"pmids\": [\"27030744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-17A and IL-17F are differentially regulated in psoriatic disease: their expression predominantly occurs in distinct T cell populations. STAT5/IL-2 signaling has opposing effects on each gene. Higher IL-17F expression is linked to greater cell proliferation. The IL17A-F locus carries a broad H3K4me3 region reflecting epigenetic plasticity.\",\n      \"method\": \"Single-cell RNA sequencing, novel cytokine-capture technique combined with ChIP-seq and RNA-seq, lesional skin tissue from psoriasis patients, in vitro culture systems with methylprednisolone treatment\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal genomic and functional methods, patient tissue plus in vitro, single lab\",\n      \"pmids\": [\"37244461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PGE2 and IL-23 plus IL-1β differentially regulate IL-17A and IL-17F in human Th17 memory cells: PGE2 induces IL-17A but not IL-17F via the EP4 receptor, promoting a switch from IL-17F to IL-17A predominant responses. IL-23 plus IL-1β preferentially induce IL-17F. The IL17A and IL17F loci have divergent epigenetic architectures in Th17 cells, with IL17A poised for preferential expression.\",\n      \"method\": \"Activated human peripheral CD4+ memory T cells and sorted Th17 memory cells, gene expression profiling, ChIP for histone marks, pharmacological EP4 receptor studies\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human primary cells with pharmacological and epigenetic mechanistic dissection, single lab\",\n      \"pmids\": [\"23800789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Fusobacterium nucleatum promotes intestinal inflammation in UC by targeting CARD3 through NOD2, which activates the IL-17F/NF-κB pathway in intestinal epithelial cells in vitro and in vivo.\",\n      \"method\": \"F. nucleatum infection of UC cell lines and mouse models in vivo, CARD3 knockdown/overexpression, NF-κB pathway reporters, IL-17F cytokine measurement by ELISA\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic in vitro and in vivo pathway dissection, single lab\",\n      \"pmids\": [\"31610014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-17A and IL-17F are both required for antimicrobial peptide production (mBD-3, CRAMP, mBD-14) and clearance of S. aureus nasal colonization in mice. Mice deficient in both IL-17A and IL-17F lost the ability to clear S. aureus; IL-17A alone was sufficient for nasal mBD-3 production ex vivo.\",\n      \"method\": \"IL-17A/IL-17F double-deficient mice, S. aureus nasal colonization model, ex vivo nasal tissue supernatant antimicrobial activity assay, antimicrobial peptide expression (RT-PCR, ELISA)\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined antimicrobial peptide mechanistic readout, single lab\",\n      \"pmids\": [\"27736775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In a TDI-induced steroid-insensitive asthma model, anti-IL-17F (but not anti-IL-17A) treatment ameliorated airway hyperresponsiveness and bronchial neutrophilia with decreased Th17 responses, while anti-IL-17A increased AHR and eosinophilia with amplified Th2 responses. Recombinant IL-17A and IL-17F showed opposite effects consistent with the antibody results, demonstrating distinct and opposing biological roles in this context.\",\n      \"method\": \"TDI-sensitized BALB/c mice, anti-IL-17A and anti-IL-17F monoclonal antibody treatment, recombinant IL-17A and IL-17F administration, airway hyperresponsiveness measurement, bronchoalveolar lavage cell counts, cytokine profiling\",\n      \"journal\": \"The European respiratory journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo antibody neutralization and recombinant protein rescue, mechanistic dissection of distinct roles, single lab\",\n      \"pmids\": [\"30655284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-17A and IL-17F enhance in vitro osteogenic differentiation and bone formation from human periosteal-derived cells (hPDCs). Dual neutralization of IL-17A and IL-17F by bimekizumab blocked T cell supernatant-induced and patient AS serum-induced in vitro bone formation more deeply than neutralization of either cytokine alone. Osteogenic blockade may involve increased expression of the Wnt antagonist DKK1.\",\n      \"method\": \"Human periosteal-derived cell osteogenic differentiation assay, recombinant IL-17A and IL-17F, T cell supernatants, AS patient serum, bimekizumab and monospecific antibody treatment, DKK1 expression assay\",\n      \"journal\": \"RMD open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro biomimetic model with recombinant proteins and patient samples, mechanistic DKK1 link, single lab\",\n      \"pmids\": [\"32723833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-17A and IL-17F induce autophagy in RAW 264.7 macrophages, as shown by LC3B-II accumulation, enhanced autophagic flux, increased autophagosome number/size, and acidic vesicular organelle formation. IL-17F was more efficient than IL-17A in promoting autophagy. IL-17F treatment significantly decreased intracellular counts of Mycobacterium terrae in macrophages.\",\n      \"method\": \"RAW 264.7 macrophage culture, recombinant IL-17A and IL-17F, LC3B-II Western blot, confocal microscopy of autophagosome formation, autophagic flux assay, intracellular M. terrae colony-forming unit counting\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal autophagy assays with functional bacterial clearance readout, single lab\",\n      \"pmids\": [\"26796276\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-17F is a disulfide-linked homodimeric cytokine (and component of an IL-17A/F heterodimer) produced predominantly by Th17 cells that signals through the IL-17RA/IL-17RC receptor heterodimer—with IL-17RC forming a 2:1 complex with IL-17F as revealed by crystal structure—requiring the adaptors Act1 and TRAF6 to activate NF-κB and MAPK (Raf1-MEK-ERK-p90RSK-CREB) cascades in epithelial and stromal cells, inducing proinflammatory chemokines (CXCL1, CXCL5, IL-8/CXCL8, IP-10/CXCL10, CCL20), cytokines (IL-6, IL-11), and antimicrobial peptides; its expression at the IL17A–IL17F locus is controlled by a lineage-specific cis-regulatory element (CNS2) that recruits p300 and JMJD3 and is epigenetically marked by H3K4me3 and H3K27 acetylation in Th17 cells, with STAT5/IL-2 signaling differentially regulating IL-17F versus IL-17A; in vivo, IL-17F plays non-redundant roles distinct from IL-17A in driving neutrophilic airway inflammation, colitis (partly via regulation of intestinal microbiota and Treg induction), crescentic glomerulonephritis, and osteogenic differentiation, and a natural loss-of-function variant (H161R) acts as an endogenous IL-17F antagonist.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL-17F is a proinflammatory cytokine produced by Th17 cells that drives neutrophilic tissue inflammation and antimicrobial defense through a dedicated IL-17 receptor signaling axis [#2, #15]. It exists as a disulfide-linked homodimer and also pairs with IL-17A to form an IL-17A/F heterodimer, all of which are secreted by differentiated Th17 cells [#0]. IL-17F signals through the IL-17RA/IL-17RC receptor heterodimer—binding IL-17RC with affinity comparable to IL-17A while engaging IL-17RA distinctly—and a crystal structure of the IL-17RC extracellular domain bound to IL-17F shows a symmetrical 2:1 IL-17RC:cytokine complex that competes with IL-17RA, defining a basis for IL-17RA-independent signaling [#1, #14]. IL-17F-induced gene expression requires IL-17RA, IL-17RC, the adaptor Act1, and TRAF6, and IL-17RC is induced into complex with IL-17RA rather than pre-associated [#2, #3]. Downstream, IL-17F activates the Raf1-MEK-ERK-p90RSK/MSK1-CREB cascade and NF-κB/IκBζ-dependent transcription in epithelial and stromal cells to induce chemokines (CXCL10/IP-10, IL-8, CXCL1, CXCL5, CCL20), cytokines (IL-6, IL-11), and antimicrobial peptides (DEFB4, S100A7) [#7, #8, #11, #19]. In vivo, IL-17F plays roles distinct from and sometimes opposing IL-17A, driving allergic and infection-associated airway neutrophilia, DSS colitis (via regulation of the intestinal microbiota and Treg balance), and crescentic glomerulonephritis through CXCL1/CXCL5-mediated neutrophil recruitment [#2, #12, #19, #24]. Its expression at the shared IL17A–IL17F locus is governed by a Th17-lineage cis-regulatory element (CNS2) that recruits p300 and JMJD3 and bears H3K4me3/H3K27 acetylation marks, with STAT5/IL-2 and prostaglandin/cytokine inputs differentially partitioning IL-17F versus IL-17A output [#5, #6, #21]. A natural His161Arg variant is signaling-dead and dominantly blocks wild-type IL-17F, acting as an endogenous antagonist [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that IL-17F is a functional epithelial-activating cytokine and identified a natural loss-of-function variant, revealing both its signaling output and a mechanism of endogenous antagonism.\",\n      \"evidence\": \"Recombinant wild-type and H161R IL-17F on bronchial epithelial cells with MAPK and cytokine/chemokine readouts\",\n      \"pmids\": [\"16630936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the receptor or adaptor requirements\", \"Structural basis of H161R antagonism not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the proximal MAPK signaling route by which IL-17F drives chemokine output, establishing the Raf1-MEK-ERK-p90RSK-CREB cascade.\",\n      \"evidence\": \"Kinase inhibitors, dominant-negative Raf1, and siRNA of p90RSK/CREB in bronchial epithelial cells measuring IP-10\",\n      \"pmids\": [\"17418381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor engagement upstream of Raf1 not addressed\", \"Single cell type\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed that IL-17A and IL-17F form a heterodimer in addition to homodimers and are co-secreted by Th17 cells, and that IL-17F locus activation is epigenetically programmed during Th17 differentiation.\",\n      \"evidence\": \"Overexpression/recombinant protein assays plus ChIP for histone marks at the IL-17/IL-17F locus in Th17 cells\",\n      \"pmids\": [\"17452998\", \"18025225\", \"17218320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor specificity of the heterodimer not yet defined\", \"Regulatory element driving locus marks not identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the receptor and adaptor requirements for IL-17F signaling and demonstrated non-redundant in vivo roles distinct from IL-17A in airway and intestinal inflammation.\",\n      \"evidence\": \"IL-17F knockout and transgenic mice, genetic knockouts of IL-17RA/TRAF6/Act1 in vitro, SPR binding, and allergen/DSS colitis models\",\n      \"pmids\": [\"18411338\", \"18684971\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of receptor binding unresolved\", \"Mechanism of opposing IL-17A vs IL-17F colitis phenotypes unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended the MAPK signaling model to IL-11 induction and showed reciprocal regulation in which IL-17A suppresses IL-17F production through IL-17RA.\",\n      \"evidence\": \"MSK1/CREB siRNA and inhibitors in epithelial cells; Il17a-/- mice and IL-17RA-deficient cells measuring IL-17F\",\n      \"pmids\": [\"19251839\", \"19542376\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of IL-17A-mediated feedback on IL-17F transcription not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established IL-17RC as absolutely required for IL-17F signaling and showed the receptor complex is ligand-induced rather than pre-formed, with the SEFIR domain essential for transduction but not assembly.\",\n      \"evidence\": \"Il17rc-/- mice, cell-surface complex-formation assays, and SEFIR domain mutagenesis\",\n      \"pmids\": [\"20231694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative receptor stoichiometry not resolved at this stage\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the CNS2 cis-regulatory element as the locus-control mechanism that physically contacts the Il17/Il17f promoters and recruits histone-modifying enzymes to enable selective Th17 transcription.\",\n      \"evidence\": \"CNS2 targeted deletion in mice with chromosome-conformation assays and ChIP for p300 and JMJD3\",\n      \"pmids\": [\"22244845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CNS2 differentially partitions IL-17F vs IL-17A output not fully defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved the mechanism of IL-17F-driven tissue injury in glomerulonephritis as CXCL1/CXCL5-mediated neutrophil recruitment, and demonstrated requirement in NAFLD inflammation.\",\n      \"evidence\": \"Il17f-/- mice, neutralizing antibodies, adoptive transfer, neutrophil depletion in nephritis models; MCDD diet model\",\n      \"pmids\": [\"27030744\", \"26895034\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific source of pathogenic IL-17F in chronic models not fully dissected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined an IL-17RA-independent IL-17F/IL-17RC signaling axis on epithelium with context-dependent protective vs pathogenic outcomes, and identified IκBζ as a transcriptional mediator of psoriasis-associated genes.\",\n      \"evidence\": \"Il17ra-/-/Il17a-/-/Il17f-/- mice in airway infection/inflammation models; IκBζ siRNA and p38/NF-κB inhibitors in keratinocytes\",\n      \"pmids\": [\"28813677\", \"27576147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of IL-17RA-independent signaling not yet shown\", \"Determinants of protective vs pathogenic outcome unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed IL-17F shapes the intestinal microbiota and Treg balance, providing a mechanistic basis for its selective pathogenicity in colitis distinct from IL-17A.\",\n      \"evidence\": \"Il17f-/- mice, adoptive transfer into Rag2-/-, anti-IL-17F antibody, and 16S microbiota analysis\",\n      \"pmids\": [\"29915298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct antimicrobial-protein targets mediating microbiota shifts not enumerated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the structural mechanism of receptor engagement, showing IL-17RC forms a symmetric 2:1 complex with IL-17F that competes with IL-17RA, rationalizing IL-17RA-independent signaling.\",\n      \"evidence\": \"X-ray crystallography of IL-17RC ectodomain:IL-17F complex with SPR/ITC biophysics\",\n      \"pmids\": [\"32187518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the 2:1 complex transduces signal in the absence of IL-17RA not resolved\", \"No structure of the full signaling complex\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Refined the picture of differential IL-17A vs IL-17F regulation in human disease, linking distinct T cell populations, STAT5/IL-2 signaling, and locus epigenetic architecture to selective IL-17F output.\",\n      \"evidence\": \"Single-cell RNA-seq, cytokine-capture with ChIP-seq/RNA-seq on psoriatic skin and in vitro culture\",\n      \"pmids\": [\"37244461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal regulators distinguishing the two genes not fully isolated\", \"Single-lab dataset\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the IL-17F/IL-17RC 2:1 complex transduces signal independently of IL-17RA, and what determines whether IL-17F output is protective versus pathogenic in a given tissue, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of an IL-17RA-independent signaling-competent complex\", \"Tissue-context switch between protective and pathogenic IL-17F responses unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 4, 7, 9, 10, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 12, 19, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 7, 11, 14]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 6, 11, 21]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IL17RC\", \"IL17RA\", \"IL17A\", \"TRAF6\", \"ACT1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}