{"gene":"IL17F","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2008,"finding":"IL-17F regulates proinflammatory gene expression and requires IL-17 receptor A (IL-17RA), TRAF6, and Act1 for signaling, similar to IL-17A. In vivo, IL-17F-deficient mice showed defective airway neutrophilia in allergen challenge and reduced colitis severity, while IL-17A-deficient mice showed opposite effects, demonstrating distinct non-redundant roles.","method":"Genetic loss-of-function (IL-17F and IL-17A knockout mice), in vitro signaling assays, in vivo allergen challenge and colitis models","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — reciprocal KO mice with defined cellular phenotypes plus in vitro signaling pathway identification, replicated across multiple disease models","pmids":["18411338"],"is_preprint":false},{"year":2009,"finding":"IL-17F utilizes IL-17RA and IL-17RC as its receptor complex and employs Act1 and TRAF6 as signal transducers to induce expression of pro-inflammatory cytokines and chemokines in multiple cell types. IL-17F can be secreted as homodimers or as heterodimers with IL-17A.","method":"Review synthesizing receptor binding studies, signaling pathway analyses, and cytokine secretion assays","journal":"Cytokine","confidence":"High","confidence_rationale":"Tier 2 — synthesis of multiple orthogonal studies establishing receptor usage and signal transducers","pmids":["19233684"],"is_preprint":false},{"year":2020,"finding":"Crystal structure of extracellular domain of human IL-17RC in complex with IL-17F revealed that IL-17RC forms a symmetrical 2:1 complex with IL-17F (two receptor molecules per cytokine dimer), competing with IL-17RA for cytokine binding. IL-17A and IL-17A/F heterodimers also form 2:1 complexes with IL-17RC, suggesting IL-17RA-independent IL-17F signaling pathways.","method":"X-ray crystallography, biophysical binding assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with biophysical validation revealing unexpected receptor stoichiometry","pmids":["32187518"],"is_preprint":false},{"year":2012,"finding":"A conserved noncoding sequence 2 (CNS2) element physically interacts with both Il17 and Il17f gene promoters and is necessary and sufficient for their selective transcription in Th17 cells. CNS2-mediated recruitment of histone-modifying enzymes p300 and JMJD3 drives chromatin remodeling at the Il17-Il17f locus, and targeted deletion of CNS2 impairs RORγt-driven IL-17 and IL-17F expression.","method":"Targeted deletion of cis-regulatory element, chromatin immunoprecipitation, in vitro Th17 differentiation, EAE model","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — genetic deletion with multiple orthogonal methods (ChIP, in vitro, in vivo EAE) in single rigorous study","pmids":["22244845"],"is_preprint":false},{"year":2008,"finding":"IL-17F induces IL-8 production in normal human epidermal keratinocytes via ERK1/2 phosphorylation (MEK-ERK pathway). Intradermal injection of IL-17F in mouse skin induced IL-8 mRNA expression and ERK1/2 phosphorylation, causing marked neutrophil infiltration that was blocked by anti-IL-8 antibody.","method":"In vitro keratinocyte stimulation with kinase inhibitors, in vivo intradermal injection, ELISA, real-time PCR, histology, immunohistochemistry","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including pharmacological inhibition and in vivo confirmation with antibody blockade","pmids":["18830271"],"is_preprint":false},{"year":2009,"finding":"IL-17F induces IL-11 expression in bronchial epithelial cells through the Raf1-MEK1/2-ERK1/2-MSK1-CREB signaling pathway. siRNA knockdown of MSK1 inhibited CREB activation and IL-11 expression, and siRNAs targeting both MSK1 and CREB blocked IL-17F-induced IL-11 production.","method":"siRNA knockdown, kinase inhibitors, phosphorylation assays (Western blot), ELISA, real-time PCR","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 2 — RNAi combined with pharmacological inhibition and multiple readouts establishing signaling pathway","pmids":["19251839"],"is_preprint":false},{"year":2017,"finding":"IL-17F stimulation induces IκBζ expression in human keratinocytes via p38 MAPK and NF-κB signaling pathways. IκBζ in turn acts as a key regulator of IL-17F-inducible psoriasis-associated genes including DEFB4/hBD2, S100A7, CCL20, IL-8, and CHI3L1, as demonstrated by siRNA silencing of IκBζ.","method":"siRNA knockdown of IκBζ, pharmacological inhibitors of p38 MAPK and NF-κB, real-time PCR, Western blot","journal":"Experimental dermatology","confidence":"High","confidence_rationale":"Tier 2 — siRNA knockdown combined with pharmacological inhibition and multiple target gene readouts","pmids":["27576147"],"is_preprint":false},{"year":2017,"finding":"IL-17F induces IL-6 production in airway smooth muscle cells (ASMCs) via the TAK1-NF-κB signaling pathway. siRNA knockdown of TAK1 abolished IL-17F-induced phosphorylation of NF-κB p65, and pharmacological inhibition of either TAK1 or NF-κB blocked IL-6 production.","method":"siRNA knockdown, pharmacological inhibitors (5Z-7-oxozeaenol, BAY 11-7082), Western blot for phosphorylation, ELISA, real-time PCR","journal":"Immunity, inflammation and disease","confidence":"High","confidence_rationale":"Tier 2 — RNAi with pharmacological validation establishing TAK1-NF-κB pathway","pmids":["28474507"],"is_preprint":false},{"year":2001,"finding":"IL-17F (initially named ML-1) is a novel cytokine expressed in activated CD4+ T cells, basophils, and mast cells that induces IL-6, IL-8, and ICAM-1 expression in primary bronchial epithelial cells. The ICAM-1 induction effect was not blocked by saturating IL-17, suggesting IL-17F signals through a distinct receptor.","method":"Gene cloning from human cDNA, transient transfection of COS-7 cells, ELISA, flow cytometry for ICAM-1, antibody blocking assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — original discovery paper with functional in vitro assays and receptor discrimination experiment","pmids":["11591768"],"is_preprint":false},{"year":2010,"finding":"IL-17F induces IL-6 production in normal human epidermal keratinocytes (NHEKs) in a time-dependent manner, an effect blocked by a chimeric IL-17 receptor inhibitor. Intradermal injection of IL-17F in mouse skin upregulated IL-6 mRNA 3.2-fold. IL-6 induction by IL-17F was higher than that induced by TNF-α or IL-17A.","method":"In vitro keratinocyte stimulation, ELISA, real-time PCR, in vivo intradermal injection in mice, immunohistochemistry","journal":"Archives of dermatological research","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo concordant data, single lab","pmids":["20148256"],"is_preprint":false},{"year":2018,"finding":"IL-17F promotes osteoblast differentiation through a mechanism involving IL-17RA/IL-17RC receptor signaling that activates Runx2 and C/EBP-β while causing β-catenin degradation, acting independently of canonical Wnt signaling. siRNA knockdown of IL-17Ra and IL-17Rc decreased expression of Act2, Runx2, and C/EBP-β.","method":"siRNA knockdown of IL-17Ra and IL-17Rc, Western blot for signaling proteins, gene expression analysis in MC3T3-E1 cells","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 — RNAi with signaling protein readouts, single lab, single cell line","pmids":["30010083"],"is_preprint":false},{"year":2012,"finding":"T-lymphocytes produce IL-17F to stimulate osteoblast maturation during the early phase of fracture repair. In vitro studies showed IL-17F alone stimulates osteoblast maturation, and Rag1-/- mice (lacking lymphocytes) showed impaired fracture healing associated with IL-17F deficiency.","method":"Rag1-/- mouse model, in vitro osteoblast stimulation, histology, µCT, biomechanical testing, quantitative gene expression","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function mouse model with in vitro confirmation, single lab","pmids":["22768215"],"is_preprint":false},{"year":2018,"finding":"IL-17F suppression but not IL-17A suppression protects against colitis by inducing regulatory T cells through modification of intestinal microbiota. IL-17F drives expression of antimicrobial proteins that normally suppress Clostridium cluster XIVa (Treg-inducing bacteria); loss of IL-17F increases this Clostridium cluster and expands intestinal Tregs.","method":"IL-17F and IL-17A knockout mice, T cell transfer colitis model in Rag2-/- mice, anti-IL-17F and anti-IL-17A antibody treatment, microbiome analysis, Treg quantification","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches (KO mice, antibody neutralization, T cell transfer, microbiome analysis) in single rigorous study","pmids":["29915298"],"is_preprint":false},{"year":2016,"finding":"IL-17F-deficient mice are protected from tissue injury in acute crescentic glomerulonephritis (GN). CD4+ T cell-derived IL-17F drives renal neutrophil infiltration by inducing expression of CXCL1 and CXCL5 in kidney cells. Neutrophil depletion abolished the difference between IL-17F-deficient and wild-type nephritic mice.","method":"IL-17F knockout mice, neutralizing antibodies, adoptive transfer into Rag1-/- mice, neutrophil depletion, cytokine induction assays in kidney cells","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches (KO, antibody, adoptive transfer, depletion) establishing mechanism","pmids":["27030744"],"is_preprint":false},{"year":2017,"finding":"The IL-17F/IL-17RC signaling axis (independent of IL-17RA) promotes respiratory allergy and exacerbates lower airway inflammation by Aspergillus or Pseudomonas infection, while in upper airway Staphylococcus aureus infection the same axis mediates protection. Mice lacking IL-17RA but retaining IL-17RC showed exacerbated lower airway pathology driven by IL-17F.","method":"IL-17A KO, IL-17F KO, and IL-17RA KO mice in infection and allergy models; genetic epistasis between receptor and cytokine knockouts","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple KO mouse lines across multiple disease models","pmids":["28813677"],"is_preprint":false},{"year":2009,"finding":"IL-17A controls IL-17F production via IL-17RA signaling; IL-17A-deficient mice showed elevated plasma IL-17F levels and splenocytes from these mice produced more IL-17F in response to IL-23. Adding recombinant IL-17A to IL-17A-deficient splenocyte cultures reduced IL-17F mRNA and protein, an effect absent in IL-17RA-deficient cells.","method":"IL-17A KO and IL-17RA KO mice, ex vivo splenocyte differentiation, cytokine measurement by ELISA and PCR, recombinant cytokine add-back","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function mouse models with mechanistic add-back experiment, single lab","pmids":["19542376"],"is_preprint":false},{"year":2011,"finding":"IL-17F production by macrophages requires MyD88 adapter protein downstream of TLR4/LPS signaling. C5a amplifies IL-17F production via C5aR through PI3K-Akt pathway phosphorylation at threonine 308. Pharmacological inhibition of PI3K-Akt greatly reduced IL-17F production and mRNA.","method":"MyD88 knockout macrophages, pharmacological PI3K-Akt inhibitors, Western blot for Akt phosphorylation, ELISA, endotoxemia and CLP in vivo models","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — genetic KO combined with pharmacological inhibition and in vivo models, identifying signaling pathway","pmids":["21859896"],"is_preprint":false},{"year":2019,"finding":"Fusobacterium nucleatum promotes intestinal inflammation in ulcerative colitis by targeting CARD3 through NOD2, which activates the IL-17F/NF-κB signaling pathway. Mechanistically, F. nucleatum infection upregulates CARD3 expression, which feeds into IL-17F-driven NF-κB activation.","method":"In vitro and in vivo F. nucleatum infection models, NF-κB pathway analysis, gene expression studies","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 3 — mechanistic pathway placement with in vitro and in vivo data, single lab","pmids":["31610014"],"is_preprint":false},{"year":2019,"finding":"IL-17F, rather than IL-17A, mediates airway inflammation and neutrophilia in a toluene diisocyanate (TDI)-induced steroid-insensitive asthma model. Anti-IL-17F ameliorated TDI-induced airway hyperresponsiveness and neutrophilia, while anti-IL-17A worsened airway eosinophil recruitment and mucus production.","method":"TDI-induced asthma mouse model, anti-IL-17F and anti-IL-17A monoclonal antibody blockade, recombinant cytokine administration, AHR measurement, differential cell counts","journal":"The European respiratory journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal antibody blockade experiments with recombinant cytokine controls establishing distinct functional roles","pmids":["30655284"],"is_preprint":false},{"year":2023,"finding":"IL-17A and IL-17F expression occurs predominantly in distinct T cell populations in psoriatic disease. STAT5/IL-2 signaling exerts opposing effects on each gene: promoting IL-17A while suppressing IL-17F. The IL17A-F locus shows a broad H3K4me3 region, and higher IL17F expression is linked to greater cell proliferation.","method":"Single-cell RNA sequencing, chromatin immunoprecipitation sequencing, novel cytokine-capture technique combined with ChIP-seq and RNA-seq in lesional psoriatic skin and in vitro systems","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 1/2 — multiple orthogonal methods (scRNA-seq, ChIP-seq, cytokine-capture) in single rigorous study","pmids":["37244461"],"is_preprint":false},{"year":2015,"finding":"IL-17F induces autophagy in RAW 264.7 macrophages, promoting LC3B-II accumulation, increased autophagosome formation, and enhanced autophagic flux. IL-17F was considerably more efficient than IL-17A in promoting autophagy and significantly decreased intracellular counts of Mycobacterium terrae.","method":"LC3B-II Western blot, confocal microscopy for intracellular LC3B redistribution, acidic vesicular organelle staining, colony-forming unit assays","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 3 — multiple readouts for autophagy, single lab, no pathway mechanistic dissection","pmids":["26796276"],"is_preprint":false},{"year":2020,"finding":"IL-17F directly stimulates osteogenic differentiation of human periosteal cells, and T helper 17/γδ T cell supernatants also potently stimulate in vitro bone formation. Dual inhibition of IL-17A and IL-17F (bimekizumab) blocked osteogenic differentiation more deeply than either alone, potentially via increased expression of Wnt antagonist DKK1.","method":"Human periosteum-derived cell model of osteogenic differentiation, recombinant cytokines, T cell supernatants, AS patient serum, antibody blockade, DKK1 expression analysis","journal":"RMD open","confidence":"Medium","confidence_rationale":"Tier 2 — human cell model with multiple cytokine conditions and antibody blockade, single lab","pmids":["32723833"],"is_preprint":false},{"year":2020,"finding":"IL-17F and IL-17A act through macrophage orchestration (M2-like polarization) rather than directly on lung cancer cells to promote tumor growth, proliferation, and angiogenesis. Conditioned media from IL-17A/F-stimulated macrophages promoted lung cancer cell migration and in vivo tumor growth via enhanced M2 macrophage polarization.","method":"Flow cytometry for macrophage polarization, ELISA, SRB viability assay, CAM in vivo assay, conditioned media experiments","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods with in vitro and in vivo data, single lab","pmids":["32227296"],"is_preprint":false},{"year":2015,"finding":"IL-17F induces NF-κB phospho-p65 and ERK phosphorylation in human gingival fibroblasts, and promotes IL-6, CXCL8, and CCL20 production through IL-17 receptor signaling. siRNA knockdown of IL-17R reduced these inflammatory cytokine outputs.","method":"siRNA knockdown of IL-17R, Western blot for NF-κB and ERK phosphorylation, RT-PCR and ELISA for cytokine production","journal":"Inflammation","confidence":"Medium","confidence_rationale":"Tier 2 — RNAi with signaling and functional readouts, single lab","pmids":["25384562"],"is_preprint":false}],"current_model":"IL-17F is a disulfide-linked homodimeric (or IL-17A/F heterodimeric) cytokine that signals through an IL-17RA/IL-17RC heterodimeric receptor complex (with a structurally defined 2:1 IL-17RC:IL-17F stoichiometry enabling IL-17RA-independent signaling) via Act1 and TRAF6 to activate NF-κB (through TAK1-p65) and MAPK (MEK-ERK-MSK1) cascades, inducing pro-inflammatory mediators including IL-6, IL-8, CCL20, and IL-11 in epithelial cells, fibroblasts, smooth muscle cells, and macrophages; its transcription in Th17 cells is controlled by a CNS2 cis-element recruiting p300 and JMJD3 and is differentially regulated from IL-17A through STAT5 and prostaglandin E2 signaling; in vivo IL-17F has non-redundant roles from IL-17A in driving airway neutrophilia, colitis via antimicrobial protein-microbiome interactions, renal injury via CXCL1/CXCL5-dependent neutrophil recruitment, and osteoblast differentiation via Runx2/C/EBP-β independently of canonical Wnt signaling."},"narrative":{"teleology":[{"year":2001,"claim":"The initial cloning of IL-17F (ML-1) established it as a novel T cell–derived cytokine capable of inducing IL-6, IL-8, and ICAM-1 in epithelial cells, and receptor-blocking experiments indicated it signals through a receptor distinct from IL-17A's.","evidence":"Gene cloning, COS-7 transfection, ELISA, and anti-IL-17 blocking in bronchial epithelial cells","pmids":["11591768"],"confidence":"High","gaps":["Receptor identity unknown at this stage","Intracellular signaling cascade not mapped","In vivo function not tested"]},{"year":2008,"claim":"Genetic knockout studies resolved a key question about whether IL-17F and IL-17A are functionally redundant, revealing distinct and sometimes opposing roles: IL-17F-deficient mice showed defective airway neutrophilia but protection from colitis, whereas IL-17A-deficient mice showed the opposite pattern; signaling was shown to require IL-17RA, Act1, and TRAF6.","evidence":"IL-17F and IL-17A KO mice in allergen challenge and colitis models, in vitro signaling assays","pmids":["18411338"],"confidence":"High","gaps":["Molecular basis for opposing in vivo roles unclear","Receptor complex composition not fully defined","Act1/TRAF6 downstream branching pathways not dissected"]},{"year":2008,"claim":"Mapping of the MEK–ERK signaling arm downstream of IL-17F established that IL-17F induces IL-8 through ERK1/2 phosphorylation in keratinocytes, with in vivo confirmation showing ERK-dependent neutrophil recruitment in skin.","evidence":"Kinase inhibitors in keratinocytes, intradermal injection in mice, anti-IL-8 blocking","pmids":["18830271"],"confidence":"High","gaps":["Transcription factor targets downstream of ERK not identified","Relative contribution of MAPK vs NF-κB arms unclear"]},{"year":2009,"claim":"The full receptor complex (IL-17RA/IL-17RC) and the ability of IL-17F to form both homodimers and IL-17A/F heterodimers were consolidated, defining the ligand–receptor system.","evidence":"Synthesis of receptor binding studies and cytokine secretion assays","pmids":["19233684"],"confidence":"High","gaps":["Structural basis of receptor–ligand interaction unknown","Stoichiometry of receptor complex not determined"]},{"year":2009,"claim":"Extension of the MAPK signaling cascade revealed that IL-17F induces IL-11 through a Raf1–MEK1/2–ERK1/2–MSK1–CREB pathway in bronchial epithelial cells, identifying MSK1 as a critical kinase node.","evidence":"siRNA knockdown of MSK1/CREB combined with kinase inhibitors in bronchial epithelial cells","pmids":["19251839"],"confidence":"High","gaps":["Whether MSK1–CREB axis is shared with IL-17A signaling unknown","Upstream selectivity for Raf1 isoform not tested"]},{"year":2012,"claim":"Identification of the CNS2 cis-regulatory element resolved how IL-17F transcription is selectively activated in Th17 cells: CNS2 contacts both Il17a and Il17f promoters and recruits the histone acetyltransferase p300 and demethylase JMJD3 to remodel chromatin, with CNS2 deletion impairing RORγt-driven expression.","evidence":"Targeted CNS2 deletion, ChIP, in vitro Th17 differentiation, EAE model","pmids":["22244845"],"confidence":"High","gaps":["Whether CNS2 differentially regulates IL-17A vs IL-17F not resolved","Upstream signals targeting p300/JMJD3 to CNS2 not identified"]},{"year":2012,"claim":"A physiological role for IL-17F in bone biology was established: T lymphocyte–derived IL-17F stimulates osteoblast maturation, and lymphocyte-deficient Rag1−/− mice with impaired fracture healing had reduced IL-17F.","evidence":"Rag1−/− mouse fracture model, in vitro osteoblast stimulation","pmids":["22768215"],"confidence":"Medium","gaps":["Direct IL-17F KO not used in fracture model","Downstream osteogenic signaling pathway not dissected"]},{"year":2016,"claim":"IL-17F was shown to drive renal injury in crescentic glomerulonephritis through CD4+ T cell–derived IL-17F inducing CXCL1/CXCL5 in kidney cells, recruiting neutrophils as the effector mechanism.","evidence":"IL-17F KO mice, neutralizing antibodies, adoptive transfer into Rag1−/− mice, neutrophil depletion","pmids":["27030744"],"confidence":"High","gaps":["Specific kidney cell type responding to IL-17F not defined","Relative contribution of IL-17F vs IL-17A in chronic GN unclear"]},{"year":2017,"claim":"Two parallel signaling branches were fully delineated: IL-17F activates TAK1–NF-κB (p65) in airway smooth muscle cells to produce IL-6, and activates p38 MAPK/NF-κB to induce IκBζ in keratinocytes, which then controls psoriasis-associated gene expression (DEFB4, S100A7, CCL20).","evidence":"siRNA knockdown of TAK1 and IκBζ, pharmacological inhibitors, Western blot for phospho-p65 and p38, ELISA","pmids":["28474507","27576147"],"confidence":"High","gaps":["Whether IκBζ is a universal mediator of IL-17F target genes outside keratinocytes unknown","TAK1 activation mechanism by Act1/TRAF6 not structurally resolved"]},{"year":2017,"claim":"Genetic epistasis using IL-17RA KO, IL-17F KO, and IL-17A KO mice demonstrated that IL-17F can signal through IL-17RC independently of IL-17RA, with this axis driving lower airway pathology in allergy and infection while mediating upper airway protection.","evidence":"Multiple KO mouse lines across Aspergillus, Pseudomonas, and Staphylococcus infection/allergy models","pmids":["28813677"],"confidence":"High","gaps":["Signaling adaptors downstream of IL-17RC alone not identified","Basis for tissue-specific protective vs pathogenic outcomes unclear"]},{"year":2018,"claim":"A microbiome-dependent mechanism was uncovered for IL-17F in colitis: IL-17F promotes antimicrobial protein expression that suppresses Treg-inducing Clostridium cluster XIVa; loss of IL-17F expands these bacteria and intestinal Tregs, conferring protection.","evidence":"IL-17F and IL-17A KO mice, T cell transfer colitis in Rag2−/− mice, anti-IL-17F antibody, microbiome analysis","pmids":["29915298"],"confidence":"High","gaps":["Specific antimicrobial proteins mediating effect not identified","Whether human microbiome responds similarly unknown"]},{"year":2018,"claim":"The osteogenic signaling pathway was mechanistically resolved: IL-17F activates Runx2 and C/EBPβ via IL-17RA/IL-17RC while promoting β-catenin degradation, establishing a Wnt-independent osteoblast differentiation pathway.","evidence":"siRNA knockdown of IL-17Ra/IL-17Rc in MC3T3-E1 cells, Western blot for signaling proteins","pmids":["30010083"],"confidence":"Medium","gaps":["Mechanism of β-catenin degradation not determined","Single cell line limits generalizability"]},{"year":2019,"claim":"Reciprocal antibody blockade in steroid-insensitive asthma definitively separated IL-17F from IL-17A functions: anti-IL-17F ameliorated airway neutrophilia and hyperresponsiveness, while anti-IL-17A worsened eosinophilic inflammation.","evidence":"TDI-induced asthma mouse model, anti-IL-17F and anti-IL-17A mAbs, recombinant cytokine controls","pmids":["30655284"],"confidence":"High","gaps":["Mechanism by which IL-17A blockade worsens eosinophilia unclear","Downstream effectors distinguishing neutrophilic vs eosinophilic pathways not identified"]},{"year":2020,"claim":"The structural basis of IL-17F receptor engagement was solved: crystal structure revealed a symmetric 2:1 IL-17RC:IL-17F complex where two IL-17RC molecules bind one IL-17F dimer, competing with IL-17RA and providing a structural rationale for IL-17RA-independent signaling.","evidence":"X-ray crystallography and biophysical binding assays","pmids":["32187518"],"confidence":"High","gaps":["Full ternary complex with IL-17RA not structurally resolved","How 2:1 vs 1:1:1 stoichiometry triggers different downstream signals unknown"]},{"year":2023,"claim":"Differential transcriptional regulation of IL-17F vs IL-17A was resolved at the epigenomic level: STAT5/IL-2 signaling suppresses IL-17F while promoting IL-17A, and the two cytokines are predominantly expressed in distinct T cell populations within psoriatic lesions.","evidence":"Single-cell RNA-seq, ChIP-seq, cytokine-capture assay in psoriatic skin and in vitro systems","pmids":["37244461"],"confidence":"High","gaps":["Transcription factors directly binding IL17F promoter vs CNS2 downstream of STAT5 not identified","Whether distinct T cell populations reflect stable lineage commitment or plasticity unknown"]},{"year":null,"claim":"Key unresolved questions include the full signaling cascade downstream of IL-17RC alone (without IL-17RA), the specific antimicrobial proteins through which IL-17F shapes the intestinal microbiome, and the structural basis of the complete ternary IL-17F/IL-17RA/IL-17RC signaling complex.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of ternary IL-17F/IL-17RA/IL-17RC complex","Antimicrobial effectors downstream of IL-17F in gut not identified","IL-17RA-independent signaling adaptors unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,4,5,7,8,9,13]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,8]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,4,6,12,13,14,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,5,7,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10,11,21]}],"complexes":["IL-17A/F heterodimer","IL-17F homodimer"],"partners":["IL17RA","IL17RC","TRAF6","TRAF3IP2","TAK1","IL17A"],"other_free_text":[]},"mechanistic_narrative":"IL-17F is a pro-inflammatory cytokine of the IL-17 family, produced primarily by Th17 cells, γδ T cells, and macrophages, that drives neutrophilic inflammation, antimicrobial defense, and tissue remodeling through signaling pathways distinct from yet overlapping with those of the closely related IL-17A. IL-17F signals as a homodimer or IL-17A/F heterodimer through an IL-17RA/IL-17RC receptor complex—with a structurally defined 2:1 IL-17RC:IL-17F stoichiometry that also permits IL-17RA-independent signaling—engaging the adaptor Act1 and TRAF6 to activate NF-κB (via TAK1–p65) and MAPK (MEK–ERK–MSK1–CREB) cascades, thereby inducing IL-6, IL-8, CCL20, IL-11, and antimicrobial peptides in epithelial cells, fibroblasts, smooth muscle cells, and macrophages [PMID:11591768, PMID:18411338, PMID:32187518, PMID:28474507, PMID:19251839, PMID:27576147]. Transcription of IL17F in Th17 cells requires a CNS2 cis-regulatory element that recruits p300 and JMJD3 for chromatin remodeling, and is differentially regulated from IL-17A by STAT5/IL-2 signaling, which suppresses IL-17F while promoting IL-17A [PMID:22244845, PMID:37244461]. In vivo, IL-17F has non-redundant roles from IL-17A: it mediates airway neutrophilia in steroid-insensitive asthma, drives colitis through antimicrobial protein–microbiota interactions that suppress Treg-inducing Clostridium species, promotes renal injury via CXCL1/CXCL5-dependent neutrophil recruitment, and stimulates osteoblast differentiation through Runx2/C/EBPβ independently of canonical Wnt signaling [PMID:30655284, PMID:29915298, PMID:27030744, PMID:30010083]."},"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). 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investigations","url":"https://pubmed.ncbi.nlm.nih.gov/26232893","citation_count":19,"is_preprint":false},{"pmid":"27021337","id":"PMC_27021337","title":"Association between IL17A and IL17F polymorphisms and risk of Henoch-Schonlein purpura in Chinese children.","date":"2016","source":"Rheumatology international","url":"https://pubmed.ncbi.nlm.nih.gov/27021337","citation_count":18,"is_preprint":false},{"pmid":"23283937","id":"PMC_23283937","title":"Intracellular two-phase Ca2+ release and apoptosis controlled by TRP-ML1 channel activity in coronary arterial myocytes.","date":"2013","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/23283937","citation_count":18,"is_preprint":false},{"pmid":"26083022","id":"PMC_26083022","title":"Involvement of IL17A, IL17F and IL23R Polymorphisms in Colorectal Cancer Therapy.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26083022","citation_count":18,"is_preprint":false},{"pmid":"29874787","id":"PMC_29874787","title":"Inflammatory Dietary Pattern, IL-17F Genetic Variant, and the Risk of Colorectal Cancer.","date":"2018","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/29874787","citation_count":18,"is_preprint":false},{"pmid":"25613064","id":"PMC_25613064","title":"Serum IL-17F combined with VEGF as potential diagnostic biomarkers for oral squamous cell carcinoma.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25613064","citation_count":18,"is_preprint":false},{"pmid":"35861937","id":"PMC_35861937","title":"Inhibiting IL-17A and IL-17F in Rheumatic Disease: Therapeutics Help to Elucidate Disease Mechanisms.","date":"2022","source":"Current rheumatology reports","url":"https://pubmed.ncbi.nlm.nih.gov/35861937","citation_count":18,"is_preprint":false},{"pmid":"21196754","id":"PMC_21196754","title":"Significant association between IL-17F promoter region polymorphism and susceptibility to asthma in a Korean population.","date":"2010","source":"International archives of allergy and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21196754","citation_count":18,"is_preprint":false},{"pmid":"2273061","id":"PMC_2273061","title":"Improved coupling between proliferation-arrest and differentiation-induction in ML-1 human myeloblastic leukemia cells.","date":"1990","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/2273061","citation_count":18,"is_preprint":false},{"pmid":"30010083","id":"PMC_30010083","title":"A two phase regulation of bone regeneration: IL-17F mediates osteoblastogenesis via C/EBP-β in vitro.","date":"2018","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/30010083","citation_count":17,"is_preprint":false},{"pmid":"26119194","id":"PMC_26119194","title":"Investigating the Association of IL-17A and IL-17F with Susceptibility to Pre-eclampsia in Iranian Women.","date":"2015","source":"Iranian journal of immunology : IJI","url":"https://pubmed.ncbi.nlm.nih.gov/26119194","citation_count":17,"is_preprint":false},{"pmid":"39531733","id":"PMC_39531733","title":"The roles of interleukin (IL)-17A and IL-17F in hidradenitis suppurativa pathogenesis: evidence from human in vitro preclinical experiments and clinical samples.","date":"2025","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/39531733","citation_count":16,"is_preprint":false},{"pmid":"26558270","id":"PMC_26558270","title":"Genetic Polymorphisms of IL-17F and TRAF3IP2 Could Be Predictive Factors of the Long-Term Effect of Infliximab against Crohn's Disease.","date":"2015","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/26558270","citation_count":16,"is_preprint":false},{"pmid":"27591988","id":"PMC_27591988","title":"IL17A and IL17F Gene Polymorphism Association with Psoriasis Risk and Response to Treatment in a Polish Population.","date":"2016","source":"Dermatology (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/27591988","citation_count":16,"is_preprint":false},{"pmid":"31941804","id":"PMC_31941804","title":"Interleukin 17A and IL-17F Expression and Functional Responses in Rheumatoid Arthritis and Peripheral Spondyloarthritis.","date":"2020","source":"The Journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/31941804","citation_count":16,"is_preprint":false},{"pmid":"31831764","id":"PMC_31831764","title":"The IL17F His161Arg polymorphism, a potential risk locus for psoriasis, increases serum levels of interleukin-17F in an Asian population.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31831764","citation_count":15,"is_preprint":false},{"pmid":"28474507","id":"PMC_28474507","title":"IL-17F induces IL-6 via TAK1-NFκB pathway in airway smooth muscle cells.","date":"2017","source":"Immunity, inflammation and disease","url":"https://pubmed.ncbi.nlm.nih.gov/28474507","citation_count":15,"is_preprint":false},{"pmid":"30399422","id":"PMC_30399422","title":"The combined effect of IL-17F and CCL20 gene polymorphism in susceptibility to multiple sclerosis in Egypt.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/30399422","citation_count":15,"is_preprint":false},{"pmid":"26667835","id":"PMC_26667835","title":"The IL17F and IL17RA Genetic Variants Increase Risk of Cerebral Malaria in Two African Populations.","date":"2015","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/26667835","citation_count":14,"is_preprint":false},{"pmid":"25384562","id":"PMC_25384562","title":"Overexpression and Potential Regulatory Role of IL-17F in Pathogenesis of Chronic Periodontitis.","date":"2015","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/25384562","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52287,"output_tokens":5997,"usd":0.123408},"stage2":{"model":"claude-opus-4-6","input_tokens":9655,"output_tokens":3904,"usd":0.218812},"total_usd":0.34222,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-17F regulates proinflammatory gene expression and requires IL-17 receptor A (IL-17RA), TRAF6, and Act1 for signaling, similar to IL-17A. In vivo, IL-17F-deficient mice showed defective airway neutrophilia in allergen challenge and reduced colitis severity, while IL-17A-deficient mice showed opposite effects, demonstrating distinct non-redundant roles.\",\n      \"method\": \"Genetic loss-of-function (IL-17F and IL-17A knockout mice), in vitro signaling assays, in vivo allergen challenge and colitis models\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal KO mice with defined cellular phenotypes plus in vitro signaling pathway identification, replicated across multiple disease models\",\n      \"pmids\": [\"18411338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-17F utilizes IL-17RA and IL-17RC as its receptor complex and employs Act1 and TRAF6 as signal transducers to induce expression of pro-inflammatory cytokines and chemokines in multiple cell types. IL-17F can be secreted as homodimers or as heterodimers with IL-17A.\",\n      \"method\": \"Review synthesizing receptor binding studies, signaling pathway analyses, and cytokine secretion assays\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — synthesis of multiple orthogonal studies establishing receptor usage and signal transducers\",\n      \"pmids\": [\"19233684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of extracellular domain of human IL-17RC in complex with IL-17F revealed that IL-17RC forms a symmetrical 2:1 complex with IL-17F (two receptor molecules per cytokine dimer), competing with IL-17RA for cytokine binding. IL-17A and IL-17A/F heterodimers also form 2:1 complexes with IL-17RC, suggesting IL-17RA-independent IL-17F signaling pathways.\",\n      \"method\": \"X-ray crystallography, biophysical binding assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with biophysical validation revealing unexpected receptor stoichiometry\",\n      \"pmids\": [\"32187518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A conserved noncoding sequence 2 (CNS2) element physically interacts with both Il17 and Il17f gene promoters and is necessary and sufficient for their selective transcription in Th17 cells. CNS2-mediated recruitment of histone-modifying enzymes p300 and JMJD3 drives chromatin remodeling at the Il17-Il17f locus, and targeted deletion of CNS2 impairs RORγt-driven IL-17 and IL-17F expression.\",\n      \"method\": \"Targeted deletion of cis-regulatory element, chromatin immunoprecipitation, in vitro Th17 differentiation, EAE model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic deletion with multiple orthogonal methods (ChIP, in vitro, in vivo EAE) in single rigorous study\",\n      \"pmids\": [\"22244845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-17F induces IL-8 production in normal human epidermal keratinocytes via ERK1/2 phosphorylation (MEK-ERK pathway). Intradermal injection of IL-17F in mouse skin induced IL-8 mRNA expression and ERK1/2 phosphorylation, causing marked neutrophil infiltration that was blocked by anti-IL-8 antibody.\",\n      \"method\": \"In vitro keratinocyte stimulation with kinase inhibitors, in vivo intradermal injection, ELISA, real-time PCR, histology, immunohistochemistry\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including pharmacological inhibition and in vivo confirmation with antibody blockade\",\n      \"pmids\": [\"18830271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-17F induces IL-11 expression in bronchial epithelial cells through the Raf1-MEK1/2-ERK1/2-MSK1-CREB signaling pathway. siRNA knockdown of MSK1 inhibited CREB activation and IL-11 expression, and siRNAs targeting both MSK1 and CREB blocked IL-17F-induced IL-11 production.\",\n      \"method\": \"siRNA knockdown, kinase inhibitors, phosphorylation assays (Western blot), ELISA, real-time PCR\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNAi combined with pharmacological inhibition and multiple readouts establishing signaling pathway\",\n      \"pmids\": [\"19251839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-17F stimulation induces IκBζ expression in human keratinocytes via p38 MAPK and NF-κB signaling pathways. IκBζ in turn acts as a key regulator of IL-17F-inducible psoriasis-associated genes including DEFB4/hBD2, S100A7, CCL20, IL-8, and CHI3L1, as demonstrated by siRNA silencing of IκBζ.\",\n      \"method\": \"siRNA knockdown of IκBζ, pharmacological inhibitors of p38 MAPK and NF-κB, real-time PCR, Western blot\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — siRNA knockdown combined with pharmacological inhibition and multiple target gene readouts\",\n      \"pmids\": [\"27576147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-17F induces IL-6 production in airway smooth muscle cells (ASMCs) via the TAK1-NF-κB signaling pathway. siRNA knockdown of TAK1 abolished IL-17F-induced phosphorylation of NF-κB p65, and pharmacological inhibition of either TAK1 or NF-κB blocked IL-6 production.\",\n      \"method\": \"siRNA knockdown, pharmacological inhibitors (5Z-7-oxozeaenol, BAY 11-7082), Western blot for phosphorylation, ELISA, real-time PCR\",\n      \"journal\": \"Immunity, inflammation and disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNAi with pharmacological validation establishing TAK1-NF-κB pathway\",\n      \"pmids\": [\"28474507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-17F (initially named ML-1) is a novel cytokine expressed in activated CD4+ T cells, basophils, and mast cells that induces IL-6, IL-8, and ICAM-1 expression in primary bronchial epithelial cells. The ICAM-1 induction effect was not blocked by saturating IL-17, suggesting IL-17F signals through a distinct receptor.\",\n      \"method\": \"Gene cloning from human cDNA, transient transfection of COS-7 cells, ELISA, flow cytometry for ICAM-1, antibody blocking assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original discovery paper with functional in vitro assays and receptor discrimination experiment\",\n      \"pmids\": [\"11591768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-17F induces IL-6 production in normal human epidermal keratinocytes (NHEKs) in a time-dependent manner, an effect blocked by a chimeric IL-17 receptor inhibitor. Intradermal injection of IL-17F in mouse skin upregulated IL-6 mRNA 3.2-fold. IL-6 induction by IL-17F was higher than that induced by TNF-α or IL-17A.\",\n      \"method\": \"In vitro keratinocyte stimulation, ELISA, real-time PCR, in vivo intradermal injection in mice, immunohistochemistry\",\n      \"journal\": \"Archives of dermatological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo concordant data, single lab\",\n      \"pmids\": [\"20148256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-17F promotes osteoblast differentiation through a mechanism involving IL-17RA/IL-17RC receptor signaling that activates Runx2 and C/EBP-β while causing β-catenin degradation, acting independently of canonical Wnt signaling. siRNA knockdown of IL-17Ra and IL-17Rc decreased expression of Act2, Runx2, and C/EBP-β.\",\n      \"method\": \"siRNA knockdown of IL-17Ra and IL-17Rc, Western blot for signaling proteins, gene expression analysis in MC3T3-E1 cells\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi with signaling protein readouts, single lab, single cell line\",\n      \"pmids\": [\"30010083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"T-lymphocytes produce IL-17F to stimulate osteoblast maturation during the early phase of fracture repair. In vitro studies showed IL-17F alone stimulates osteoblast maturation, and Rag1-/- mice (lacking lymphocytes) showed impaired fracture healing associated with IL-17F deficiency.\",\n      \"method\": \"Rag1-/- mouse model, in vitro osteoblast stimulation, histology, µCT, biomechanical testing, quantitative gene expression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function mouse model with in vitro confirmation, single lab\",\n      \"pmids\": [\"22768215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-17F suppression but not IL-17A suppression protects against colitis by inducing regulatory T cells through modification of intestinal microbiota. IL-17F drives expression of antimicrobial proteins that normally suppress Clostridium cluster XIVa (Treg-inducing bacteria); loss of IL-17F increases this Clostridium cluster and expands intestinal Tregs.\",\n      \"method\": \"IL-17F and IL-17A knockout mice, T cell transfer colitis model in Rag2-/- mice, anti-IL-17F and anti-IL-17A antibody treatment, microbiome analysis, Treg quantification\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches (KO mice, antibody neutralization, T cell transfer, microbiome analysis) in single rigorous study\",\n      \"pmids\": [\"29915298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-17F-deficient mice are protected from tissue injury in acute crescentic glomerulonephritis (GN). CD4+ T cell-derived IL-17F drives renal neutrophil infiltration by inducing expression of CXCL1 and CXCL5 in kidney cells. Neutrophil depletion abolished the difference between IL-17F-deficient and wild-type nephritic mice.\",\n      \"method\": \"IL-17F knockout mice, neutralizing antibodies, adoptive transfer into Rag1-/- mice, neutrophil depletion, cytokine induction assays in kidney cells\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches (KO, antibody, adoptive transfer, depletion) establishing mechanism\",\n      \"pmids\": [\"27030744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The IL-17F/IL-17RC signaling axis (independent of IL-17RA) promotes respiratory allergy and exacerbates lower airway inflammation by Aspergillus or Pseudomonas infection, while in upper airway Staphylococcus aureus infection the same axis mediates protection. Mice lacking IL-17RA but retaining IL-17RC showed exacerbated lower airway pathology driven by IL-17F.\",\n      \"method\": \"IL-17A KO, IL-17F KO, and IL-17RA KO mice in infection and allergy models; genetic epistasis between receptor and cytokine knockouts\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple KO mouse lines across multiple disease models\",\n      \"pmids\": [\"28813677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-17A controls IL-17F production via IL-17RA signaling; IL-17A-deficient mice showed elevated plasma IL-17F levels and splenocytes from these mice produced more IL-17F in response to IL-23. Adding recombinant IL-17A to IL-17A-deficient splenocyte cultures reduced IL-17F mRNA and protein, an effect absent in IL-17RA-deficient cells.\",\n      \"method\": \"IL-17A KO and IL-17RA KO mice, ex vivo splenocyte differentiation, cytokine measurement by ELISA and PCR, recombinant cytokine add-back\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function mouse models with mechanistic add-back experiment, single lab\",\n      \"pmids\": [\"19542376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-17F production by macrophages requires MyD88 adapter protein downstream of TLR4/LPS signaling. C5a amplifies IL-17F production via C5aR through PI3K-Akt pathway phosphorylation at threonine 308. Pharmacological inhibition of PI3K-Akt greatly reduced IL-17F production and mRNA.\",\n      \"method\": \"MyD88 knockout macrophages, pharmacological PI3K-Akt inhibitors, Western blot for Akt phosphorylation, ELISA, endotoxemia and CLP in vivo models\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO combined with pharmacological inhibition and in vivo models, identifying signaling pathway\",\n      \"pmids\": [\"21859896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Fusobacterium nucleatum promotes intestinal inflammation in ulcerative colitis by targeting CARD3 through NOD2, which activates the IL-17F/NF-κB signaling pathway. Mechanistically, F. nucleatum infection upregulates CARD3 expression, which feeds into IL-17F-driven NF-κB activation.\",\n      \"method\": \"In vitro and in vivo F. nucleatum infection models, NF-κB pathway analysis, gene expression studies\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic pathway placement with in vitro and in vivo data, single lab\",\n      \"pmids\": [\"31610014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17F, rather than IL-17A, mediates airway inflammation and neutrophilia in a toluene diisocyanate (TDI)-induced steroid-insensitive asthma model. Anti-IL-17F ameliorated TDI-induced airway hyperresponsiveness and neutrophilia, while anti-IL-17A worsened airway eosinophil recruitment and mucus production.\",\n      \"method\": \"TDI-induced asthma mouse model, anti-IL-17F and anti-IL-17A monoclonal antibody blockade, recombinant cytokine administration, AHR measurement, differential cell counts\",\n      \"journal\": \"The European respiratory journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal antibody blockade experiments with recombinant cytokine controls establishing distinct functional roles\",\n      \"pmids\": [\"30655284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-17A and IL-17F expression occurs predominantly in distinct T cell populations in psoriatic disease. STAT5/IL-2 signaling exerts opposing effects on each gene: promoting IL-17A while suppressing IL-17F. The IL17A-F locus shows a broad H3K4me3 region, and higher IL17F expression is linked to greater cell proliferation.\",\n      \"method\": \"Single-cell RNA sequencing, chromatin immunoprecipitation sequencing, novel cytokine-capture technique combined with ChIP-seq and RNA-seq in lesional psoriatic skin and in vitro systems\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — multiple orthogonal methods (scRNA-seq, ChIP-seq, cytokine-capture) in single rigorous study\",\n      \"pmids\": [\"37244461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-17F induces autophagy in RAW 264.7 macrophages, promoting LC3B-II accumulation, increased autophagosome formation, and enhanced autophagic flux. IL-17F was considerably more efficient than IL-17A in promoting autophagy and significantly decreased intracellular counts of Mycobacterium terrae.\",\n      \"method\": \"LC3B-II Western blot, confocal microscopy for intracellular LC3B redistribution, acidic vesicular organelle staining, colony-forming unit assays\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — multiple readouts for autophagy, single lab, no pathway mechanistic dissection\",\n      \"pmids\": [\"26796276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-17F directly stimulates osteogenic differentiation of human periosteal cells, and T helper 17/γδ T cell supernatants also potently stimulate in vitro bone formation. Dual inhibition of IL-17A and IL-17F (bimekizumab) blocked osteogenic differentiation more deeply than either alone, potentially via increased expression of Wnt antagonist DKK1.\",\n      \"method\": \"Human periosteum-derived cell model of osteogenic differentiation, recombinant cytokines, T cell supernatants, AS patient serum, antibody blockade, DKK1 expression analysis\",\n      \"journal\": \"RMD open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human cell model with multiple cytokine conditions and antibody blockade, single lab\",\n      \"pmids\": [\"32723833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-17F and IL-17A act through macrophage orchestration (M2-like polarization) rather than directly on lung cancer cells to promote tumor growth, proliferation, and angiogenesis. Conditioned media from IL-17A/F-stimulated macrophages promoted lung cancer cell migration and in vivo tumor growth via enhanced M2 macrophage polarization.\",\n      \"method\": \"Flow cytometry for macrophage polarization, ELISA, SRB viability assay, CAM in vivo assay, conditioned media experiments\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods with in vitro and in vivo data, single lab\",\n      \"pmids\": [\"32227296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-17F induces NF-κB phospho-p65 and ERK phosphorylation in human gingival fibroblasts, and promotes IL-6, CXCL8, and CCL20 production through IL-17 receptor signaling. siRNA knockdown of IL-17R reduced these inflammatory cytokine outputs.\",\n      \"method\": \"siRNA knockdown of IL-17R, Western blot for NF-κB and ERK phosphorylation, RT-PCR and ELISA for cytokine production\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi with signaling and functional readouts, single lab\",\n      \"pmids\": [\"25384562\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-17F is a disulfide-linked homodimeric (or IL-17A/F heterodimeric) cytokine that signals through an IL-17RA/IL-17RC heterodimeric receptor complex (with a structurally defined 2:1 IL-17RC:IL-17F stoichiometry enabling IL-17RA-independent signaling) via Act1 and TRAF6 to activate NF-κB (through TAK1-p65) and MAPK (MEK-ERK-MSK1) cascades, inducing pro-inflammatory mediators including IL-6, IL-8, CCL20, and IL-11 in epithelial cells, fibroblasts, smooth muscle cells, and macrophages; its transcription in Th17 cells is controlled by a CNS2 cis-element recruiting p300 and JMJD3 and is differentially regulated from IL-17A through STAT5 and prostaglandin E2 signaling; in vivo IL-17F has non-redundant roles from IL-17A in driving airway neutrophilia, colitis via antimicrobial protein-microbiome interactions, renal injury via CXCL1/CXCL5-dependent neutrophil recruitment, and osteoblast differentiation via Runx2/C/EBP-β independently of canonical Wnt signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL-17F is a pro-inflammatory cytokine of the IL-17 family, produced primarily by Th17 cells, γδ T cells, and macrophages, that drives neutrophilic inflammation, antimicrobial defense, and tissue remodeling through signaling pathways distinct from yet overlapping with those of the closely related IL-17A. IL-17F signals as a homodimer or IL-17A/F heterodimer through an IL-17RA/IL-17RC receptor complex—with a structurally defined 2:1 IL-17RC:IL-17F stoichiometry that also permits IL-17RA-independent signaling—engaging the adaptor Act1 and TRAF6 to activate NF-κB (via TAK1–p65) and MAPK (MEK–ERK–MSK1–CREB) cascades, thereby inducing IL-6, IL-8, CCL20, IL-11, and antimicrobial peptides in epithelial cells, fibroblasts, smooth muscle cells, and macrophages [PMID:11591768, PMID:18411338, PMID:32187518, PMID:28474507, PMID:19251839, PMID:27576147]. Transcription of IL17F in Th17 cells requires a CNS2 cis-regulatory element that recruits p300 and JMJD3 for chromatin remodeling, and is differentially regulated from IL-17A by STAT5/IL-2 signaling, which suppresses IL-17F while promoting IL-17A [PMID:22244845, PMID:37244461]. In vivo, IL-17F has non-redundant roles from IL-17A: it mediates airway neutrophilia in steroid-insensitive asthma, drives colitis through antimicrobial protein–microbiota interactions that suppress Treg-inducing Clostridium species, promotes renal injury via CXCL1/CXCL5-dependent neutrophil recruitment, and stimulates osteoblast differentiation through Runx2/C/EBPβ independently of canonical Wnt signaling [PMID:30655284, PMID:29915298, PMID:27030744, PMID:30010083].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"The initial cloning of IL-17F (ML-1) established it as a novel T cell–derived cytokine capable of inducing IL-6, IL-8, and ICAM-1 in epithelial cells, and receptor-blocking experiments indicated it signals through a receptor distinct from IL-17A's.\",\n      \"evidence\": \"Gene cloning, COS-7 transfection, ELISA, and anti-IL-17 blocking in bronchial epithelial cells\",\n      \"pmids\": [\"11591768\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor identity unknown at this stage\", \"Intracellular signaling cascade not mapped\", \"In vivo function not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genetic knockout studies resolved a key question about whether IL-17F and IL-17A are functionally redundant, revealing distinct and sometimes opposing roles: IL-17F-deficient mice showed defective airway neutrophilia but protection from colitis, whereas IL-17A-deficient mice showed the opposite pattern; signaling was shown to require IL-17RA, Act1, and TRAF6.\",\n      \"evidence\": \"IL-17F and IL-17A KO mice in allergen challenge and colitis models, in vitro signaling assays\",\n      \"pmids\": [\"18411338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for opposing in vivo roles unclear\", \"Receptor complex composition not fully defined\", \"Act1/TRAF6 downstream branching pathways not dissected\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapping of the MEK–ERK signaling arm downstream of IL-17F established that IL-17F induces IL-8 through ERK1/2 phosphorylation in keratinocytes, with in vivo confirmation showing ERK-dependent neutrophil recruitment in skin.\",\n      \"evidence\": \"Kinase inhibitors in keratinocytes, intradermal injection in mice, anti-IL-8 blocking\",\n      \"pmids\": [\"18830271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factor targets downstream of ERK not identified\", \"Relative contribution of MAPK vs NF-κB arms unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The full receptor complex (IL-17RA/IL-17RC) and the ability of IL-17F to form both homodimers and IL-17A/F heterodimers were consolidated, defining the ligand–receptor system.\",\n      \"evidence\": \"Synthesis of receptor binding studies and cytokine secretion assays\",\n      \"pmids\": [\"19233684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of receptor–ligand interaction unknown\", \"Stoichiometry of receptor complex not determined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extension of the MAPK signaling cascade revealed that IL-17F induces IL-11 through a Raf1–MEK1/2–ERK1/2–MSK1–CREB pathway in bronchial epithelial cells, identifying MSK1 as a critical kinase node.\",\n      \"evidence\": \"siRNA knockdown of MSK1/CREB combined with kinase inhibitors in bronchial epithelial cells\",\n      \"pmids\": [\"19251839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MSK1–CREB axis is shared with IL-17A signaling unknown\", \"Upstream selectivity for Raf1 isoform not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of the CNS2 cis-regulatory element resolved how IL-17F transcription is selectively activated in Th17 cells: CNS2 contacts both Il17a and Il17f promoters and recruits the histone acetyltransferase p300 and demethylase JMJD3 to remodel chromatin, with CNS2 deletion impairing RORγt-driven expression.\",\n      \"evidence\": \"Targeted CNS2 deletion, ChIP, in vitro Th17 differentiation, EAE model\",\n      \"pmids\": [\"22244845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CNS2 differentially regulates IL-17A vs IL-17F not resolved\", \"Upstream signals targeting p300/JMJD3 to CNS2 not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"A physiological role for IL-17F in bone biology was established: T lymphocyte–derived IL-17F stimulates osteoblast maturation, and lymphocyte-deficient Rag1−/− mice with impaired fracture healing had reduced IL-17F.\",\n      \"evidence\": \"Rag1−/− mouse fracture model, in vitro osteoblast stimulation\",\n      \"pmids\": [\"22768215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct IL-17F KO not used in fracture model\", \"Downstream osteogenic signaling pathway not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"IL-17F was shown to drive renal injury in crescentic glomerulonephritis through CD4+ T cell–derived IL-17F inducing CXCL1/CXCL5 in kidney cells, recruiting neutrophils as the effector mechanism.\",\n      \"evidence\": \"IL-17F KO mice, neutralizing antibodies, adoptive transfer into Rag1−/− mice, neutrophil depletion\",\n      \"pmids\": [\"27030744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific kidney cell type responding to IL-17F not defined\", \"Relative contribution of IL-17F vs IL-17A in chronic GN unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two parallel signaling branches were fully delineated: IL-17F activates TAK1–NF-κB (p65) in airway smooth muscle cells to produce IL-6, and activates p38 MAPK/NF-κB to induce IκBζ in keratinocytes, which then controls psoriasis-associated gene expression (DEFB4, S100A7, CCL20).\",\n      \"evidence\": \"siRNA knockdown of TAK1 and IκBζ, pharmacological inhibitors, Western blot for phospho-p65 and p38, ELISA\",\n      \"pmids\": [\"28474507\", \"27576147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IκBζ is a universal mediator of IL-17F target genes outside keratinocytes unknown\", \"TAK1 activation mechanism by Act1/TRAF6 not structurally resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Genetic epistasis using IL-17RA KO, IL-17F KO, and IL-17A KO mice demonstrated that IL-17F can signal through IL-17RC independently of IL-17RA, with this axis driving lower airway pathology in allergy and infection while mediating upper airway protection.\",\n      \"evidence\": \"Multiple KO mouse lines across Aspergillus, Pseudomonas, and Staphylococcus infection/allergy models\",\n      \"pmids\": [\"28813677\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling adaptors downstream of IL-17RC alone not identified\", \"Basis for tissue-specific protective vs pathogenic outcomes unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A microbiome-dependent mechanism was uncovered for IL-17F in colitis: IL-17F promotes antimicrobial protein expression that suppresses Treg-inducing Clostridium cluster XIVa; loss of IL-17F expands these bacteria and intestinal Tregs, conferring protection.\",\n      \"evidence\": \"IL-17F and IL-17A KO mice, T cell transfer colitis in Rag2−/− mice, anti-IL-17F antibody, microbiome analysis\",\n      \"pmids\": [\"29915298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific antimicrobial proteins mediating effect not identified\", \"Whether human microbiome responds similarly unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The osteogenic signaling pathway was mechanistically resolved: IL-17F activates Runx2 and C/EBPβ via IL-17RA/IL-17RC while promoting β-catenin degradation, establishing a Wnt-independent osteoblast differentiation pathway.\",\n      \"evidence\": \"siRNA knockdown of IL-17Ra/IL-17Rc in MC3T3-E1 cells, Western blot for signaling proteins\",\n      \"pmids\": [\"30010083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of β-catenin degradation not determined\", \"Single cell line limits generalizability\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Reciprocal antibody blockade in steroid-insensitive asthma definitively separated IL-17F from IL-17A functions: anti-IL-17F ameliorated airway neutrophilia and hyperresponsiveness, while anti-IL-17A worsened eosinophilic inflammation.\",\n      \"evidence\": \"TDI-induced asthma mouse model, anti-IL-17F and anti-IL-17A mAbs, recombinant cytokine controls\",\n      \"pmids\": [\"30655284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which IL-17A blockade worsens eosinophilia unclear\", \"Downstream effectors distinguishing neutrophilic vs eosinophilic pathways not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The structural basis of IL-17F receptor engagement was solved: crystal structure revealed a symmetric 2:1 IL-17RC:IL-17F complex where two IL-17RC molecules bind one IL-17F dimer, competing with IL-17RA and providing a structural rationale for IL-17RA-independent signaling.\",\n      \"evidence\": \"X-ray crystallography and biophysical binding assays\",\n      \"pmids\": [\"32187518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full ternary complex with IL-17RA not structurally resolved\", \"How 2:1 vs 1:1:1 stoichiometry triggers different downstream signals unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Differential transcriptional regulation of IL-17F vs IL-17A was resolved at the epigenomic level: STAT5/IL-2 signaling suppresses IL-17F while promoting IL-17A, and the two cytokines are predominantly expressed in distinct T cell populations within psoriatic lesions.\",\n      \"evidence\": \"Single-cell RNA-seq, ChIP-seq, cytokine-capture assay in psoriatic skin and in vitro systems\",\n      \"pmids\": [\"37244461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factors directly binding IL17F promoter vs CNS2 downstream of STAT5 not identified\", \"Whether distinct T cell populations reflect stable lineage commitment or plasticity unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the full signaling cascade downstream of IL-17RC alone (without IL-17RA), the specific antimicrobial proteins through which IL-17F shapes the intestinal microbiome, and the structural basis of the complete ternary IL-17F/IL-17RA/IL-17RC signaling complex.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of ternary IL-17F/IL-17RA/IL-17RC complex\", \"Antimicrobial effectors downstream of IL-17F in gut not identified\", \"IL-17RA-independent signaling adaptors unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 4, 5, 7, 8, 9, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 4, 6, 12, 13, 14, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 5, 7, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 11, 21]}\n    ],\n    \"complexes\": [\n      \"IL-17A/F heterodimer\",\n      \"IL-17F homodimer\"\n    ],\n    \"partners\": [\n      \"IL17RA\",\n      \"IL17RC\",\n      \"TRAF6\",\n      \"TRAF3IP2\",\n      \"TAK1\",\n      \"IL17A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}