{"gene":"IL17C","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2000,"finding":"IL-17C was cloned and shown to stimulate release of TNF-α and IL-1β from the monocytic cell line THP-1, and to bind THP-1 cells by FACS analysis. IL-17C does not bind the human IL-17 receptor extracellular domain and does not induce IL-6 from fibroblasts, distinguishing it from IL-17A.","method":"Recombinant protein expression, cytokine release assay (ELISA), FACS binding assay, IL-17 receptor binding assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and functional assays in cell lines, single lab, multiple orthogonal methods","pmids":["10639155"],"is_preprint":false},{"year":2011,"finding":"IL-17C signals through a heterodimeric receptor complex composed of IL-17RA and IL-17RE, which is preferentially expressed on tissue epithelial cells. IL-17C acts in an autocrine manner on epithelial cells to stimulate proinflammatory cytokines, chemokines, and antimicrobial peptides. IL-17C promoted inflammation in imiquimod-induced skin inflammation but exerted protective functions in DSS-induced colitis.","method":"Receptor binding assays, gene expression analysis, knockout mouse models (imiquimod and DSS colitis models), co-immunoprecipitation of receptor complex","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated across two independent simultaneous publications, receptor complex identification, in vivo knockout models with defined phenotypes","pmids":["21993848"],"is_preprint":false},{"year":2011,"finding":"IL-17RE is the specific functional receptor for IL-17C. IL-17C signals through the IL-17RE–IL-17RA heterodimeric complex to induce antibacterial peptides and proinflammatory molecules in colon epithelial cells. IL-17C is upregulated in colon epithelial cells during Citrobacter rodentium infection, acts synergistically with IL-22 to induce antibacterial peptides, and loss of IL-17RE leads to greater bacterial burden and early mortality.","method":"Receptor identification (IL-17RE as orphan receptor for IL-17C), IL-17RE-deficient mouse model, infection model with C. rodentium, gene expression assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor identification validated with genetic knockout and in vivo infection model, replicated independently in same year","pmids":["21993849"],"is_preprint":false},{"year":2012,"finding":"IL-17C is required for regulation of acute experimental colitis (DSS model); IL-17C-deficient mice show exacerbated disease with increased IL-17 expression by γδ T cells and Th17 cells. IL-17C directly regulates the expression of the tight junction molecule occludin by colonic epithelial cells.","method":"IL-17C-deficient mouse model, DSS colitis model, gene expression analysis, tight junction protein assessment","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined cellular and molecular phenotype, multiple orthogonal readouts","pmids":["23024280"],"is_preprint":false},{"year":2013,"finding":"NOD2 activation in keratinocytes mediates Staphylococcus aureus-induced IL-17C expression via the first NF-κB binding site in the IL-17C promoter. Crohn's disease-associated NOD2 mutations (3020insC, R702W) significantly reduced NOD2-mediated IL-17C induction. IL-17C knockdown increased S. aureus survival in keratinocytes.","method":"NOD2 overexpression in HEK293 cells, IL-17C promoter reporter assay, siRNA knockdown, S. aureus infection of primary keratinocytes","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — promoter reporter assay with mutagenesis/variant analysis plus siRNA knockdown with functional bacterial survival readout, single lab with multiple orthogonal methods","pmids":["23892590"],"is_preprint":false},{"year":2013,"finding":"Keratinocyte overexpression of IL-17C drives psoriasiform skin inflammation in mice; involved skin shows epidermal hyperplasia, angiogenesis, leukocyte infiltration, and upregulation of TNF-α, IL-1α/β, IL-17A/F, IL-23p19. IL-17C and TNF-α together produce similar inflammatory gene responses in keratinocytes as IL-17A/TNF-α, indicating a positive proinflammatory feedback loop. TNF-α inhibition ameliorated the phenotype.","method":"Transgenic mouse model (keratinocyte-specific IL-17C overexpression), cytokine stimulation of primary keratinocytes, TNF-α inhibitor treatment","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — transgenic overexpression model with detailed phenotypic and molecular characterization plus pharmacological intervention, single lab","pmids":["23359500"],"is_preprint":false},{"year":2013,"finding":"IL-17C is expressed by human bronchial epithelial cells (HBECs) in response to bacterial pathogens (Pseudomonas aeruginosa, Haemophilus influenzae) and TLR3/TLR5 ligands. IL-17C enhanced inflammatory responses of respiratory epithelial cells; cigarette smoke suppressed IL-17C expression in response to bacterial infection.","method":"In vitro bacterial infection of HBECs, TLR ligand stimulation, gene expression analysis, in vivo mouse colonization model","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo experiments, single lab, multiple stimuli tested","pmids":["23221046"],"is_preprint":false},{"year":2014,"finding":"In human IBD, IL-17C production in intestinal epithelial cells is regulated by TNF-α through NF-κB, ERK1/2, and p38 pathways, and by IL-17A through Akt, MCPIP1 (Regnase-1), and C/EBPδ pathways. IL-17A strongly amplifies TNF-α-induced IL-17C production in enteroendocrine and goblet cells. IL-17C upregulates the Th17 chemoattractant CCL20 in IECs.","method":"Primary IEC stimulation, signaling pathway inhibitors, qPCR, immunoblotting, ELISA, immunohistochemistry of IBD patient tissue","journal":"Mucosal immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with multiple signaling inhibitors, single lab","pmids":["25492478"],"is_preprint":false},{"year":2014,"finding":"IL-17C expression in airway bronchial epithelial cells is induced by polyI:C via the TLR3–TRIF–NF-κB pathway. IL-17C acts in an autocrine/paracrine manner through IL-17RE to enhance expression of antimicrobial peptides (hBD2) and proinflammatory mediators (CSF3, S100A12). Knockdown of IL-17RE attenuated polyI:C-induced hBD2, CSF3, and S100A12 expression without reducing IL-17C itself.","method":"Primary normal human bronchial epithelial (NHBE) cell stimulation, pathway inhibitors (Pepinh-TRIF, BAY11, NF-κB p65 siRNA), IL-17RE siRNA knockdown, IL-17C siRNA knockdown","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal siRNA knockdowns, pharmacological inhibition, and pathway dissection in primary cells, single lab","pmids":["23944933"],"is_preprint":false},{"year":2014,"finding":"IL-36γ induces IL-17C expression in keratinocytes and IL-17C reciprocally sustains a proinflammatory self-amplifying loop with IL-36γ. IL-17C affects keratinocyte defensin gene expression only in combination with TNF-α (not alone). Both IL-36γ and IL-17C are elevated in anti-TNF-induced psoriasiform skin lesions of Crohn's disease patients and their expression levels are strongly correlated.","method":"Primary keratinocyte stimulation, qRT-PCR, immunoblotting, ELISA, immunohistochemistry of patient skin biopsies","journal":"Inflammatory bowel diseases","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, in vitro experiments with patient tissue correlation, multiple methods","pmids":["25299544"],"is_preprint":false},{"year":2015,"finding":"IL-17C is required for lethal inflammation during systemic fungal (Candida) infection; IL-17C-deficient mice show increased survival and attenuated kidney tissue damage with decreased pro-inflammatory cytokine expression despite similar fungal loads. IL-17C directly acts on renal epithelial cells in vitro to promote pro-inflammatory cytokine production.","method":"IL-17C-deficient mouse model, systemic fungal infection model, in vitro renal epithelial cell stimulation, cytokine measurement","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with in vivo and in vitro validation, single lab","pmids":["26166766"],"is_preprint":false},{"year":2016,"finding":"MCPIP1 (Regnase-1) is a negative regulator of IL-17C signaling in non-hematopoietic (epithelial) cells. MCPIP1-deficient keratinocytes show increased responsiveness to IL-17A and IL-17C stimulation. Epistasis analysis (Zc3h12a+/-Il17c-/- double mice) demonstrated that pathology in MCPIP1-deficient mice is partly dependent on IL-17C.","method":"MCPIP1 (Zc3h12a) heterozygous knockout mice, radiation bone marrow chimeras, double-knockout epistasis (Zc3h12a+/-Il17c-/-), primary keratinocyte stimulation with IL-17C","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double knockouts, bone marrow chimeras, and primary cell experiments, multiple orthogonal methods","pmids":["27920272"],"is_preprint":false},{"year":2016,"finding":"IL-17A-mediated upregulation of epithelial IL-17C amplifies chemokine (KC, MIP-2) production and neutrophil recruitment in acute P. aeruginosa pneumonia. IL-17C-deficient mice show decreased neutrophil numbers and chemokine expression. IL-17A stimulation of primary alveolar epithelial cells directly increases IL-17C expression in vitro.","method":"IL-17C-/- and IL-17A-/- mouse models, P. aeruginosa lung infection model, primary alveolar epithelial cell stimulation, cytokine/chemokine measurement","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two genetic knockout strains with in vitro mechanistic validation, single lab","pmids":["27694471"],"is_preprint":false},{"year":2016,"finding":"IL-17C/IL-17RE axis promotes TH17 cell-driven autoimmune hepatitis. IL-17C is produced by hepatocytes, and IL-17RE is expressed on liver-resident T cells. Mechanistically, IL-17C augments IL-2 expression by intrahepatic CD4+ T cells to promote NK cell activation and liver damage.","method":"IL-17C and IL-17RE knockout mouse models (Con A hepatitis model), human patient liver samples, in vitro T cell stimulation, cytokine measurement","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two genetic knockouts with mechanistic pathway (IL-2/NK axis), single lab","pmids":["27956525"],"is_preprint":false},{"year":2017,"finding":"IL-17C expression in airway epithelial cells is induced by NTHi (nontypeable Haemophilus influenzae) through TLR-2/4 signaling. IL-17C promotes neutrophil recruitment into tumors by increasing neutrophil chemokine (KC, MIP-2) expression in lung cancer cells, thereby enhancing tumor growth in a metastatic model.","method":"IL-17C-/- and TLR-2/4-/- mouse models, metastatic lung cancer model with NTHi, in vitro cytokine stimulation of lung cancer cells, neutrophil chemokine measurement","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two genetic knockouts with in vitro mechanistic validation, single lab","pmids":["28346430"],"is_preprint":false},{"year":2017,"finding":"Keratinocytes produce IL-17C during HSV-2 reactivation. IL-17RE (the IL-17C-specific receptor) is expressed on nerve fibers in human skin and sensory neurons in dorsal root ganglia. Exogenous IL-17C provided directional guidance and promoted neurite growth and branching in microfluidic devices, and IL-17C pretreatment reduced apoptosis in HSV-2-infected primary neurons.","method":"Human skin biopsy analysis, ex vivo microfluidic neurite growth assay, primary neuron apoptosis assay with recombinant IL-17C, immunostaining of human skin and DRG","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal experiments (neurite growth, apoptosis, receptor localization), single lab","pmids":["28663436"],"is_preprint":false},{"year":2017,"finding":"IL-13 negatively regulates IL-1β-induced IL-17C expression in airway epithelial cells by suppressing NF-κB-mediated transcriptional activation. IL-1β induces IL-17C through NF-κB (p65 binds IL-17C promoter at -130/-120 and -157/-147 sites); IL-13 activates JAK/STAT6 signaling to reduce p65 binding to the IL-17C promoter without affecting upstream IκBα/NF-κB activation.","method":"Primary NHBE cell stimulation, NF-κB p65 siRNA, STAT6 siRNA, JAK inhibitor (ruxolitinib), chromatin immunoprecipitation (ChIP) of IL-17C promoter, Western blot","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP analysis of IL-17C promoter binding plus siRNA knockdowns and pharmacological inhibition, multiple orthogonal methods, single lab","pmids":["29203240"],"is_preprint":false},{"year":2018,"finding":"IL-17C/IL-17RE signaling on CD4+ TH17 cells promotes TH17-driven glomerular inflammation. IL-17RE is highly expressed by CD4+ TH17 cells; loss of IL-17RE specifically prevents TH17 responses and subsequent tissue injury. Bone marrow transplantation experiments showed IL-17C is produced by tissue-resident (non-lymphocyte) cells.","method":"IL-17C-/- and IL-17RE-/- mouse models of crescentic GN and lupus nephritis, bone marrow transplantation chimeras, TH17 response assessment, human patient serum IL-17C measurement","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 / Strong — two genetic knockouts, bone marrow chimera experiments, two independent disease models, single lab","pmids":["29483158"],"is_preprint":false},{"year":2018,"finding":"Anti-IL-17C antibody MOR106 selectively binds human and mouse IL-17C and inhibits IL-17C binding to its IL-17RE receptor. MOR106 suppressed skin inflammation in IL-23-induced psoriatic and calcipotriol-induced AD mouse models, reducing T cells, neutrophils, eosinophils, TSLP, IL-33, IgE, and mast cell numbers.","method":"Neutralizing antibody generation and characterization, in vivo IL-23-induced psoriasis model, calcipotriol AD model, flaky tail mouse model, cytokine/immune cell measurements","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody-based receptor blocking with multiple in vivo models, single lab","pmids":["29474945"],"is_preprint":false},{"year":2018,"finding":"HRV-bacterial coinfection synergistically induces IL-17C expression in bronchial epithelial cells via NF-κB and p38 MAPK signaling. IL-17C induces CXCL1 release from epithelial cells, and IL-17C knockdown significantly reduces CXCL1 induction and neutrophil chemotaxis.","method":"Primary bronchial epithelial cell infection with HRV and bacteria, pharmacological inhibitors (NF-κB, p38 MAPK), IL-17C siRNA knockdown, CXCL1 ELISA, neutrophil chemotaxis assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway inhibitors plus siRNA with functional neutrophil chemotaxis readout, single lab","pmids":["30504421"],"is_preprint":false},{"year":2019,"finding":"TLR5 signaling mediates F4+ ETEC-induced IL-17C expression in porcine intestinal epithelial cells. Both ETEC infection and exogenous IL-17C increased expression of antimicrobial peptides (pBD-2) and tight junction proteins (claudin-1, claudin-2, occludin), demonstrating an autocrine/paracrine epithelial defense function.","method":"Porcine IPEC-J2 cell infection model, TLR5 signaling analysis, recombinant IL-17C stimulation, gene expression assay","journal":"Veterinary research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro pathway analysis with exogenous protein stimulation, single lab","pmids":["31221216"],"is_preprint":false},{"year":2019,"finding":"IL-17C/IL-17RE axis promotes neutrophil recruitment during acute S. pneumoniae pneumonia. IL-17RE-deficient mice showed decreased pulmonary neutrophil numbers, decreased G-CSF and TNF-α, and reduced granulocyte-monocyte progenitor (GMP) fractions. IL-17C-deficient mice also showed reduced neutrophil numbers at 24h post-infection.","method":"IL-17RE-/- and IL-17C-/- mouse models, S. pneumoniae lung infection, flow cytometry of immune cells and bone marrow progenitors, cytokine measurement","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two genetic knockouts with defined cellular phenotype, single lab","pmids":["31481409"],"is_preprint":false},{"year":2020,"finding":"Replication-dependent rhinovirus infection drives basolateral (but not apical) IL-17C protein release from differentiated airway epithelial cells. Columnar epithelial cells express more IL-17C than basal cells. Basolateral IL-17C acts in an autocrine/paracrine manner to promote basolateral CXCL1 production.","method":"Highly differentiated human bronchial epithelial (HBE) cell air-liquid interface cultures, apical HRV infection, viral replication inhibitor, separated apical/basolateral secretion analysis, enriched cell population analysis","journal":"Frontiers in cellular and infection microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — well-differentiated air-liquid interface model, multiple controls, directional secretion analysis, single lab","pmids":["32232015"],"is_preprint":false},{"year":2020,"finding":"IL-17C has a pathogenic role in kidney ischemia/reperfusion injury. IL-17C is upregulated in hypoxic kidney tubular epithelial cells. Neutralizing IL-17C antibody or IL-17RE knockout attenuated tubular injury, oxidative stress, inflammation, TH17 activation, IL-17A expression, and downstream TNF-α and IL-1β. IL-17C knockdown with siRNA decreased hypoxia-induced inflammation in kidney tubular cells, and silencing IL-17RE abrogated IL-17C effects.","method":"IL-17RE-/- mouse model, neutralizing antibody treatment, siRNA knockdown in kidney tubular cells, kidney IRI model, cytokine and oxidative stress measurements","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout plus neutralizing antibody plus siRNA knockdown with multiple orthogonal mechanistic readouts, multiple approaches converging","pmids":["32331702"],"is_preprint":false},{"year":2020,"finding":"IL-17C promotes tumor angiogenesis in colorectal cancer by inducing VEGF production via a STAT3/miR-23a-3p/SEMA6D axis. IL-17C activates STAT3 to increase miR-23a-3p expression, which suppresses SEMA6D to permit VEGF production. IL-17C-induced angiogenesis was blocked by VEGFR2 inhibitor Ki8751 in xenograft experiments.","method":"In vitro angiogenesis assay, mouse xenograft model, ELISA, siRNA gene silencing, VEGFR2 inhibitor treatment, immunostaining","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — xenograft model with pharmacological inhibition and gene silencing, single lab","pmids":["32492770"],"is_preprint":false},{"year":2020,"finding":"IL-17C amplifies epithelial inflammation through autocrine induction of IL-17C itself in keratinocytes, and promotes expression of innate cytokines, antimicrobial peptides (IL-36G, S100A7, HBD2) and chemokines (CXCL8, CXCL10, CCL5, VEGF). IL-17C depletion with anti-IL-17C antibody MOR106 significantly reduced T cells, neutrophils, and eosinophils in mouse psoriasis and AD models and downregulated inflammatory mediators in human skin explants.","method":"Primary human keratinocyte stimulation, neutralizing antibody MOR106, IL-23 psoriasis and MC903 AD mouse models, flow cytometry, human skin ex vivo explant cultures, neutrophil migration assay","journal":"Journal of the European Academy of Dermatology and Venereology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vivo models and human ex vivo confirmation, single lab","pmids":["31793105"],"is_preprint":false},{"year":2022,"finding":"Th17-derived cytokines TNF-α, IL-17A, and IL-22 synergistically enhance IL-17C expression in colonic epithelial cells. TNF-α acts through NF-κB (blocked by IκBα inhibitor), while IL-17A and IL-22 act through AP-1 in a p38 MAPK-dependent manner to amplify IL-17C expression, establishing an inflammatory amplification loop between epithelial cells and Th17 cells.","method":"Human colonic epithelial cell lines and primary colonic organoids, cytokine stimulation, pharmacological NF-κB and p38 MAPK inhibitors, qPCR","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection in primary organoids plus cell lines, single lab","pmids":["36130829"],"is_preprint":false},{"year":2022,"finding":"LL37 activates TLR8 in keratinocytes and induces IL-17C through the induction of IL-36γ. IL-36 receptor antagonistic antibody suppressed IL-17C induced by LL37, placing IL-36γ upstream of IL-17C induction in this pathway. IL-17C was not altered by blockade of TLR7/8 directly, indicating LL37 acts on IL-17C indirectly through IL-36γ.","method":"Primary keratinocyte stimulation with LL37, TLR7/8 inhibitors, IL-36 receptor antagonist antibody, psoriatic skin immunostaining, gene expression analysis","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological inhibition pathway dissection, single lab, defines upstream regulators","pmids":["36496195"],"is_preprint":false},{"year":2023,"finding":"Hypoxia-induced IL-17C upregulation in kidney tubular cells is predominantly mediated by the NF-κB pathway (IκBα/NF-κB p65 phosphorylation). ALDH2 deficiency increases NF-κB phosphorylation, leading to increased IL-17C expression during kidney IRI. NF-κB inhibition in HK-2 cells prevented the ALDH2-knockdown-induced increase in IL-17C.","method":"ALDH2-/- mouse model, kidney IRI, RNA-seq, PCR, Western blot, HK-2 cell hypoxia/reoxygenation model, ALDH2 siRNA knockdown, NF-κB inhibitor","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout plus siRNA plus pharmacological inhibition with pathway validation, single lab","pmids":["36865346"],"is_preprint":false},{"year":2023,"finding":"Delayed (post-ischemia) IL-17C neutralization has reno-protective effects on kidney IRI. IL-17C blockade attenuated diabetic nephropathy (DN), including albuminuria, mesangial matrix accumulation, and podocyte loss. Mechanistic studies showed that hypoxia or high glucose-induced IL-17C upregulation is predominantly mediated by the NF-κB pathway, and IL-17C neutralization repressed downstream pro-inflammatory cytokines and Th17/IL-17A activation.","method":"IL-17C neutralizing antibody treatment in mouse IRI and db/db diabetic nephropathy models, NF-κB p65 siRNA knockdown, HIF-1α inhibitor (YC-1), kidney function/histology assessment, cytokine measurement","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — neutralizing antibody and siRNA mechanistic validation in two disease models, single lab","pmids":["37263138"],"is_preprint":false},{"year":2024,"finding":"IL-17C is highly induced in human Fallopian tube epithelium during N. gonorrhoeae infection. Human Fallopian tubes express the IL-17C receptor on the epithelial surface. Treatment of Fallopian tube explants with purified IL-17C induces pro-inflammatory cytokine secretion and causes sloughing of the epithelium and generalized tissue damage.","method":"Human Fallopian tube ex vivo culture with N. gonorrhoeae, RNA sequencing, purified IL-17C treatment, receptor expression analysis, histological assessment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — human ex vivo model with RNA-seq, receptor localization, and purified cytokine functional assay, single lab with multiple orthogonal methods","pmids":["38704381"],"is_preprint":false},{"year":2024,"finding":"IL-17C promotes M1 macrophage polarization in neutrophilic asthma via IL-17RE. In vitro, IL-17C synergizes with IFN-γ to activate STAT1 in IL-17RE-overexpressing macrophages (Raw264.7), upregulating M1-related genes, while inhibiting IL-4-induced STAT6 activation and M2 differentiation. In vivo, deficiency of IL-17C reversed pro-inflammatory phenotypes and inhibited M1 macrophage expansion.","method":"IL-17c-/- mouse model, OVA/CFA asthma model, exogenous rmIL-17C administration, IL-17RE-overexpressing Raw264.7 cells, flow cytometry, Western blot for STAT1/STAT6","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with in vitro receptor-overexpression mechanistic validation, single lab","pmids":["39568050"],"is_preprint":false},{"year":2025,"finding":"IL-17C upregulates SMURF2 expression in keratinocytes, leading to psoriasis-like changes. SMURF2 interacts with PPP6C (by co-immunoprecipitation) and promotes its ubiquitination and degradation. Silencing SMURF2 inhibited the effects of IL-17C on keratinocytes, and SMURF2 overexpression enhanced IL-17C effects by targeting PPP6C for degradation.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown of SMURF2, lentiviral overexpression, imiquimod psoriasis mouse model, HaCaT cell stimulation with IL-17C, Western blot, flow cytometry","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-immunoprecipitation and ubiquitination assay with siRNA and overexpression validation, single lab","pmids":["40244332"],"is_preprint":false},{"year":2026,"finding":"Macrophage RhoA ablation leads to activation of Hippo pathway effectors YAP/CCN2, causing IL-17C transcription independently of the canonical ROCK pathway. IL-17C secreted by RhoA-deficient macrophages induces chondrocyte senescence (increased p53/p21, ROS, mitochondrial dysfunction, suppressed autophagy) via activation of the PI3K/AKT/mTOR pathway.","method":"Macrophage-specific RhoA conditional knockout mouse model, OA mouse model, transcriptome sequencing, Western blot, immunofluorescence, ELISA, YAP/CCN2 pathway analysis","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific conditional knockout with transcriptomic and mechanistic pathway validation, single lab","pmids":["41620554"],"is_preprint":false}],"current_model":"IL-17C is an epithelial-derived homodimeric cytokine that signals through a heterodimeric IL-17RA/IL-17RE receptor complex to act in an autocrine/paracrine manner on epithelial cells, promoting innate immune responses including antimicrobial peptide production, tight junction maintenance, and proinflammatory cytokine/chemokine expression; its expression is induced by bacterial and viral pathogens via TLR–NF-κB and related pathways, amplified by Th17 cytokines (TNF-α, IL-17A, IL-22) and IL-36γ, and negatively regulated by MCPIP1/Regnase-1 and IL-13/STAT6 signaling; beyond the epithelium, IL-17C also signals through IL-17RE on CD4+ TH17 cells to amplify adaptive TH17 responses, and its downstream effects in various tissues involve NF-κB-mediated cytokine induction, neutrophil recruitment via CXCL1/KC/MIP-2, and in specific contexts, STAT3/miR-23a-3p/SEMA6D-driven angiogenesis and SMURF2-mediated PPP6C ubiquitination."},"narrative":{"mechanistic_narrative":"IL-17C is an epithelial-derived cytokine that drives innate and adaptive inflammatory responses by signaling through a heterodimeric IL-17RA/IL-17RE receptor complex preferentially expressed on tissue epithelial cells, acting in an autocrine/paracrine fashion to induce proinflammatory cytokines, chemokines, and antimicrobial peptides [PMID:21993848, PMID:21993849]. Functionally distinct from IL-17A, it was originally identified as a cytokine that stimulates TNF-α and IL-1β release from monocytic cells and does not bind the IL-17A receptor [PMID:10639155]. At barrier surfaces it is induced by bacterial and viral pathogens through pattern-recognition and NF-κB signaling — NOD2 in keratinocytes responding to S. aureus [PMID:23892590], TLR3-TRIF-NF-κB and TLR2/4/5 routes in airway and intestinal epithelium [PMID:23944933, PMID:28346430], and NF-κB/p38 MAPK during viral-bacterial coinfection [PMID:30504421] — and reinforces epithelial defense by inducing antimicrobial peptides and maintaining tight-junction proteins such as occludin [PMID:23024280, PMID:31221216]. IL-17C participates in self-amplifying inflammatory loops: it is upregulated by Th17 cytokines (TNF-α, IL-17A, IL-22) acting via NF-κB and AP-1/p38 [PMID:36130829], reciprocally sustained by IL-36γ [PMID:25299544, PMID:36496195], and negatively regulated by MCPIP1/Regnase-1 [PMID:27920272] and by IL-13/STAT6 signaling that reduces NF-κB p65 binding to the IL-17C promoter [PMID:29203240]. Through IL-17RE on CD4+ TH17 cells it amplifies adaptive TH17-driven tissue injury [PMID:29483158], and its downstream effects span neutrophil recruitment via CXCL1/KC/MIP-2 [PMID:27694471, PMID:30504421], M1 macrophage polarization through STAT1 [PMID:39568050], and tumor angiogenesis via a STAT3/miR-23a-3p/SEMA6D axis [PMID:32492770]. These activities give IL-17C dual protective and pathogenic roles across infection, psoriasis, colitis, nephropathy, and cancer [PMID:21993849, PMID:23359500, PMID:32331702], making it a therapeutic target addressed by neutralizing antibodies [PMID:29474945, PMID:31793105].","teleology":[{"year":2000,"claim":"Established IL-17C as a distinct cytokine by showing it induces TNF-α and IL-1β from monocytic cells yet, unlike IL-17A, does not bind the IL-17 receptor or induce fibroblast IL-6.","evidence":"Recombinant protein cytokine-release assays, FACS binding, and IL-17 receptor binding assays in cell lines","pmids":["10639155"],"confidence":"Medium","gaps":["Did not identify the functional receptor","Cellular source and physiological context unaddressed"]},{"year":2011,"claim":"Defined the IL-17C receptor as the IL-17RA/IL-17RE heterodimer on epithelial cells, answering how IL-17C signals and revealing an autocrine epithelial innate-immune function with context-dependent protective and pathogenic roles.","evidence":"Receptor binding and co-IP, IL-17RE-deficient mice, imiquimod skin and DSS colitis and C. rodentium infection models","pmids":["21993848","21993849"],"confidence":"High","gaps":["Structural basis of receptor engagement not resolved","Downstream signaling components downstream of IL-17RE not fully mapped"]},{"year":2012,"claim":"Showed IL-17C maintains epithelial barrier integrity by directly regulating the tight-junction protein occludin, linking it to protection in acute colitis.","evidence":"IL-17C-deficient mice in DSS colitis with tight-junction protein assessment","pmids":["23024280"],"confidence":"High","gaps":["Direct mechanism of occludin regulation not defined","Relationship between barrier and inflammatory functions unresolved"]},{"year":2013,"claim":"Identified pathogen-sensing routes (NOD2, TLR3/5) that induce epithelial IL-17C and demonstrated its requirement for antibacterial defense and for driving psoriasiform skin inflammation.","evidence":"NOD2 promoter reporter and variant analysis, siRNA knockdown with S. aureus survival, keratinocyte-specific transgenic overexpression, HBEC infection","pmids":["23892590","23359500","23221046"],"confidence":"High","gaps":["Relative contribution of distinct PRR pathways across tissues unclear","Why the same cytokine is protective vs pathogenic not mechanistically resolved"]},{"year":2014,"claim":"Mapped upstream induction and amplification of IL-17C, showing NF-κB-driven transcription via TLR3-TRIF, Th17-cytokine amplification, and IL-36γ reciprocal loops, and CCL20-mediated TH17 chemoattraction.","evidence":"Primary NHBE/IEC/keratinocyte stimulation with siRNA, pathway inhibitors, ELISA, patient tissue immunohistochemistry","pmids":["25492478","23944933","25299544"],"confidence":"High","gaps":["Quantitative hierarchy among inducers not established","In vivo relevance of the IL-36γ loop incompletely defined"]},{"year":2015,"claim":"Demonstrated a pathogenic role for IL-17C in lethal systemic Candida infection through direct action on renal epithelial cells, dissociating immunopathology from fungal clearance.","evidence":"IL-17C-deficient mice in systemic fungal infection with in vitro renal epithelial stimulation","pmids":["26166766"],"confidence":"Medium","gaps":["Receptor dependence in this model not directly tested","Specific renal cell mediators not identified"]},{"year":2016,"claim":"Defined negative regulation by MCPIP1/Regnase-1 and showed IL-17C amplifies neutrophilic chemokine responses during bacterial pneumonia and TH17-driven hepatitis.","evidence":"Zc3h12a/Il17c epistasis double knockouts, bone marrow chimeras, IL-17C-/- and IL-17A-/- pneumonia models, Con A hepatitis models","pmids":["27920272","27694471","27956525"],"confidence":"High","gaps":["Molecular target of MCPIP1 within the IL-17C axis not specified","Tissue-specific balance of regulators unclear"]},{"year":2017,"claim":"Extended IL-17C signaling beyond epithelium to neurons and tumor settings, showing IL-17RE on sensory neurons mediates neurite guidance and IL-17C promotes tumor-associated neutrophil recruitment.","evidence":"Microfluidic neurite assays, neuron apoptosis assays, IL-17C-/- and TLR2/4-/- metastatic lung cancer models, immunostaining","pmids":["28663436","28346430"],"confidence":"Medium","gaps":["Neuronal signaling downstream of IL-17RE undefined","Direct vs indirect tumor-promoting mechanisms not separated"]},{"year":2018,"claim":"Showed IL-17RE on CD4+ TH17 cells directly amplifies adaptive TH17 responses and established IL-17C neutralization (MOR106) as therapeutically effective in skin inflammation models.","evidence":"IL-17C-/- and IL-17RE-/- glomerulonephritis/lupus models, bone marrow chimeras, neutralizing antibody in psoriasis and AD models","pmids":["29483158","29474945"],"confidence":"High","gaps":["Intracellular signaling in TH17 cells downstream of IL-17RE not mapped","Durability and specificity of antibody effects in humans not addressed"]},{"year":2017,"claim":"Identified IL-13/STAT6 as a negative regulator that suppresses NF-κB p65 binding to the IL-17C promoter without affecting upstream NF-κB activation.","evidence":"ChIP of IL-17C promoter, p65/STAT6 siRNA, JAK inhibition in primary NHBE cells","pmids":["29203240"],"confidence":"High","gaps":["Mechanism by which STAT6 blocks p65 recruitment not defined","In vivo relevance in Th2 disease not established"]},{"year":2020,"claim":"Consolidated IL-17C as a pathogenic driver in kidney injury and uncovered effector mechanisms including STAT3/miR-23a-3p/SEMA6D-driven tumor angiogenesis and directional basolateral epithelial secretion.","evidence":"IL-17RE-/- mice, neutralizing antibody, siRNA in tubular cells, kidney IRI models, CRC xenograft angiogenesis assays, air-liquid interface HBE cultures","pmids":["32331702","32492770","32232015","31793105"],"confidence":"High","gaps":["Receptor-proximal signaling driving STAT3 activation not defined","Determinants of polarized secretion unknown"]},{"year":2023,"claim":"Detailed NF-κB as the predominant transcriptional driver of hypoxia/high-glucose-induced renal IL-17C and validated delayed IL-17C neutralization as reno-protective across IRI and diabetic nephropathy.","evidence":"ALDH2-/- mice, HK-2 hypoxia model, NF-κB and HIF-1α inhibitors, p65 siRNA, neutralizing antibody in IRI and db/db models","pmids":["36865346","37263138"],"confidence":"Medium","gaps":["Link between ALDH2 deficiency and NF-κB activation incompletely defined","Translational therapeutic window in human kidney disease unknown"]},{"year":2024,"claim":"Expanded the cellular targets of IL-17C to macrophages, showing STAT1-driven M1 polarization via IL-17RE, and demonstrated direct epithelial damage in human Fallopian tube during gonococcal infection.","evidence":"IL-17c-/- asthma model, IL-17RE-overexpressing macrophages with STAT1/STAT6 analysis, human Fallopian tube explants with N. gonorrhoeae and purified IL-17C, RNA-seq","pmids":["39568050","38704381"],"confidence":"High","gaps":["How a single receptor produces distinct STAT1 vs STAT3 outputs unresolved","Mechanism of IL-17C-induced epithelial sloughing undefined"]},{"year":2025,"claim":"Identified intracellular effector consequences of IL-17C signaling, including SMURF2 upregulation driving PPP6C ubiquitination in keratinocytes and YAP/CCN2- and PI3K/AKT/mTOR-linked induction and effects in macrophage/chondrocyte contexts.","evidence":"Co-IP, ubiquitination assays, siRNA/overexpression in HaCaT and imiquimod psoriasis; macrophage RhoA conditional knockout with transcriptomics in OA model","pmids":["40244332","41620554"],"confidence":"Medium","gaps":["Single Co-IP for SMURF2-PPP6C without reciprocal/structural validation","How IL-17C links receptor engagement to SMURF2 transcription unclear"]},{"year":null,"claim":"The receptor-proximal signaling cascade that converts IL-17RA/IL-17RE engagement into distinct outputs (STAT1 vs STAT3 vs NF-κB) and the structural basis of ligand-receptor recognition remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the IL-17C/IL-17RA/IL-17RE complex","Adaptor and kinase intermediates downstream of IL-17RE not defined","Determinants of protective vs pathogenic outcomes not mechanistically explained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,22,30]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,16,24]}],"complexes":[],"partners":["IL17RE","IL17RA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P0M4","full_name":"Interleukin-17C","aliases":["Cytokine CX2"],"length_aa":197,"mass_kda":21.8,"function":"Cytokine that plays a crucial role in innate immunity of the epithelium, including to intestinal bacterial pathogens, in an autocrine manner. Stimulates the production of antibacterial peptides and pro-inflammatory molecules for host defense by signaling through the NF-kappa-B and MAPK pathways. Acts synergically with IL22 in inducing the expression of antibacterial peptides, including S100A8, S100A9, REG3A and REG3G. Synergy is also observed with TNF and IL1B in inducing DEFB2 from keratinocytes. Depending on the type of insult, may have both protective and pathogenic properties, either by maintaining epithelial homeostasis after an inflammatory challenge or by promoting inflammatory phenotype. Enhanced IL17C/IL17RE signaling may also lead to greater susceptibility to autoimmune diseases","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9P0M4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL17C","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL17C","total_profiled":1310},"omim":[{"mim_id":"614995","title":"INTERLEUKIN 17 RECEPTOR E; IL17RE","url":"https://www.omim.org/entry/614995"},{"mim_id":"606496","title":"INTERLEUKIN 17F; IL17F","url":"https://www.omim.org/entry/606496"},{"mim_id":"605658","title":"INTERLEUKIN 25; IL25","url":"https://www.omim.org/entry/605658"},{"mim_id":"605458","title":"INTERLEUKIN 17 RECEPTOR B; IL17RB","url":"https://www.omim.org/entry/605458"},{"mim_id":"604628","title":"INTERLEUKIN 17C; IL17C","url":"https://www.omim.org/entry/604628"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"endometrium 1","ntpm":1.9},{"tissue":"urinary bladder","ntpm":1.5}],"url":"https://www.proteinatlas.org/search/IL17C"},"hgnc":{"alias_symbol":["IL-17C","CX2","IL-21","MGC126884","MGC138401"],"prev_symbol":[]},"alphafold":{"accession":"Q9P0M4","domains":[{"cath_id":"2.10.90.10","chopping":"37-74_89-193","consensus_level":"high","plddt":91.7674,"start":37,"end":193}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P0M4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P0M4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P0M4-F1-predicted_aligned_error_v6.png","plddt_mean":82.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL17C","jax_strain_url":"https://www.jax.org/strain/search?query=IL17C"},"sequence":{"accession":"Q9P0M4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P0M4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P0M4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P0M4"}},"corpus_meta":[{"pmid":"21993848","id":"PMC_21993848","title":"IL-17C regulates the innate immune function of epithelial cells in an autocrine manner.","date":"2011","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21993848","citation_count":391,"is_preprint":false},{"pmid":"10639155","id":"PMC_10639155","title":"Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 cytokine family.","date":"2000","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10639155","citation_count":276,"is_preprint":false},{"pmid":"21993849","id":"PMC_21993849","title":"IL-17RE is the functional receptor for IL-17C and mediates mucosal immunity to infection with intestinal pathogens.","date":"2011","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21993849","citation_count":257,"is_preprint":false},{"pmid":"23359500","id":"PMC_23359500","title":"Keratinocyte overexpression of IL-17C promotes psoriasiform skin inflammation.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23359500","citation_count":244,"is_preprint":false},{"pmid":"17982105","id":"PMC_17982105","title":"IL-17B and IL-17C are associated with TNF-alpha production and contribute to the exacerbation of inflammatory arthritis.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17982105","citation_count":164,"is_preprint":false},{"pmid":"28346430","id":"PMC_28346430","title":"IL-17C mediates the recruitment of tumor-associated neutrophils and lung tumor growth.","date":"2017","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/28346430","citation_count":102,"is_preprint":false},{"pmid":"29474945","id":"PMC_29474945","title":"Neutralization of IL-17C Reduces Skin Inflammation in Mouse Models of Psoriasis and Atopic Dermatitis.","date":"2018","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/29474945","citation_count":102,"is_preprint":false},{"pmid":"23024280","id":"PMC_23024280","title":"Cutting edge: regulation of intestinal inflammation and barrier function by IL-17C.","date":"2012","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23024280","citation_count":82,"is_preprint":false},{"pmid":"25492478","id":"PMC_25492478","title":"Intestinal neuroendocrine cells and goblet cells are mediators of IL-17A-amplified epithelial IL-17C production in human inflammatory bowel disease.","date":"2014","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25492478","citation_count":74,"is_preprint":false},{"pmid":"27920272","id":"PMC_27920272","title":"MCPIP1/Regnase-1 Restricts IL-17A- and IL-17C-Dependent Skin Inflammation.","date":"2016","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/27920272","citation_count":71,"is_preprint":false},{"pmid":"32174926","id":"PMC_32174926","title":"IL-17C/IL-17RE: Emergence of a Unique Axis in TH17 Biology.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32174926","citation_count":70,"is_preprint":false},{"pmid":"23892590","id":"PMC_23892590","title":"The pattern recognition receptor NOD2 mediates Staphylococcus aureus-induced IL-17C expression in keratinocytes.","date":"2013","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/23892590","citation_count":63,"is_preprint":false},{"pmid":"29483158","id":"PMC_29483158","title":"IL-17C/IL-17 Receptor E Signaling in CD4+ T Cells Promotes TH17 Cell-Driven Glomerular Inflammation.","date":"2018","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/29483158","citation_count":61,"is_preprint":false},{"pmid":"25299544","id":"PMC_25299544","title":"IL-36γ sustains a proinflammatory self-amplifying loop with IL-17C in anti-TNF-induced psoriasiform skin lesions of patients with Crohn's disease.","date":"2014","source":"Inflammatory bowel diseases","url":"https://pubmed.ncbi.nlm.nih.gov/25299544","citation_count":59,"is_preprint":false},{"pmid":"23221046","id":"PMC_23221046","title":"IL-17C is a mediator of respiratory epithelial innate immune response.","date":"2013","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23221046","citation_count":58,"is_preprint":false},{"pmid":"23944933","id":"PMC_23944933","title":"Toll-like receptor-mediated airway IL-17C enhances epithelial host defense in an autocrine/paracrine manner.","date":"2014","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23944933","citation_count":56,"is_preprint":false},{"pmid":"26166766","id":"PMC_26166766","title":"IL-17C is required for lethal inflammation during systemic fungal infection.","date":"2015","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26166766","citation_count":55,"is_preprint":false},{"pmid":"28663436","id":"PMC_28663436","title":"Keratinocytes produce IL-17c to protect peripheral nervous systems during human HSV-2 reactivation.","date":"2017","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28663436","citation_count":53,"is_preprint":false},{"pmid":"25849644","id":"PMC_25849644","title":"Signaling through IL-17C/IL-17RE is dispensable for immunity to systemic, oral and cutaneous candidiasis.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25849644","citation_count":47,"is_preprint":false},{"pmid":"27984037","id":"PMC_27984037","title":"Induction of Alternative Proinflammatory Cytokines Accounts for Sustained Psoriasiform Skin Inflammation in IL-17C+IL-6KO Mice.","date":"2016","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/27984037","citation_count":45,"is_preprint":false},{"pmid":"31793105","id":"PMC_31793105","title":"IL-17C amplifies epithelial inflammation in human psoriasis and atopic eczema.","date":"2020","source":"Journal of the European Academy of Dermatology and Venereology : JEADV","url":"https://pubmed.ncbi.nlm.nih.gov/31793105","citation_count":42,"is_preprint":false},{"pmid":"27694471","id":"PMC_27694471","title":"IL-17A-mediated expression of epithelial IL-17C promotes inflammation during acute Pseudomonas aeruginosa pneumonia.","date":"2016","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27694471","citation_count":36,"is_preprint":false},{"pmid":"28526442","id":"PMC_28526442","title":"Comparative study of interleukin-17C (IL-17C) and IL-17D in large yellow croaker Larimichthys crocea reveals their similar but differential functional activity.","date":"2017","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28526442","citation_count":35,"is_preprint":false},{"pmid":"31316109","id":"PMC_31316109","title":"IL-17C-mediated innate inflammation decreases the response to PD-1 blockade in a model of Kras-driven lung cancer.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31316109","citation_count":35,"is_preprint":false},{"pmid":"25136988","id":"PMC_25136988","title":"High IL-17E and low IL-17C dermal expression identifies a fibrosis-specific motif common to morphea and systemic sclerosis.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25136988","citation_count":35,"is_preprint":false},{"pmid":"30504421","id":"PMC_30504421","title":"Rhinovirus and Bacteria Synergistically Induce IL-17C Release from Human Airway Epithelial Cells To Promote Neutrophil Recruitment.","date":"2018","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/30504421","citation_count":33,"is_preprint":false},{"pmid":"32331702","id":"PMC_32331702","title":"IL-17C has a pathogenic role in kidney ischemia/reperfusion injury.","date":"2020","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/32331702","citation_count":32,"is_preprint":false},{"pmid":"32492770","id":"PMC_32492770","title":"miR-23a-3p is a Key Regulator of IL-17C-Induced Tumor Angiogenesis in Colorectal Cancer.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32492770","citation_count":32,"is_preprint":false},{"pmid":"23834281","id":"PMC_23834281","title":"IL-17C and its receptor IL-17RA/IL-17RE identify human oral epithelial cell as an inflammatory cell in recurrent aphthous ulcer.","date":"2013","source":"Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23834281","citation_count":31,"is_preprint":false},{"pmid":"28666355","id":"PMC_28666355","title":"mRNA cap analogues substituted in the tetraphosphate chain with CX2: identification of O-to-CCl2 as the first bridging modification that confers resistance to decapping without impairing translation.","date":"2017","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/28666355","citation_count":27,"is_preprint":false},{"pmid":"34293699","id":"PMC_34293699","title":"IL-17C in human mucosal immunity: More than just a middle child.","date":"2021","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/34293699","citation_count":26,"is_preprint":false},{"pmid":"30356086","id":"PMC_30356086","title":"The roles of IL-17C in T cell-dependent and -independent inflammatory diseases.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30356086","citation_count":24,"is_preprint":false},{"pmid":"36496195","id":"PMC_36496195","title":"Cathelicidin Antimicrobial Peptide LL37 Induces Toll-Like Receptor 8 and Amplifies IL-36γ and IL-17C in Human Keratinocytes.","date":"2022","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/36496195","citation_count":24,"is_preprint":false},{"pmid":"27956525","id":"PMC_27956525","title":"IL-17C/IL-17RE Augments T Cell Function in Autoimmune Hepatitis.","date":"2016","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/27956525","citation_count":23,"is_preprint":false},{"pmid":"30776474","id":"PMC_30776474","title":"IL-17c is involved in olfactory mucosa responses to Poly(I:C) mimicking virus presence.","date":"2019","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/30776474","citation_count":21,"is_preprint":false},{"pmid":"37263138","id":"PMC_37263138","title":"IL-17C neutralization protects the kidney against acute injury and chronic injury.","date":"2023","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/37263138","citation_count":20,"is_preprint":false},{"pmid":"31221216","id":"PMC_31221216","title":"Toll-like receptor 5-mediated IL-17C expression in intestinal epithelial cells enhances epithelial host defense against F4+ ETEC infection.","date":"2019","source":"Veterinary research","url":"https://pubmed.ncbi.nlm.nih.gov/31221216","citation_count":20,"is_preprint":false},{"pmid":"31481409","id":"PMC_31481409","title":"Interleukin 17 Receptor E (IL-17RE) and IL-17C Mediate the Recruitment of Neutrophils during Acute Streptococcus pneumoniae Pneumonia.","date":"2019","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/31481409","citation_count":17,"is_preprint":false},{"pmid":"29203240","id":"PMC_29203240","title":"IL-13 regulates IL-17C expression by suppressing NF-κB-mediated transcriptional activation in airway epithelial cells.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29203240","citation_count":16,"is_preprint":false},{"pmid":"32232015","id":"PMC_32232015","title":"Rhinovirus Induces Basolateral Release of IL-17C in Highly Differentiated Airway Epithelial Cells.","date":"2020","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32232015","citation_count":16,"is_preprint":false},{"pmid":"24013453","id":"PMC_24013453","title":"IL-17C expression in nasal epithelial cells of chronic rhinosinusitis with nasal polyposis.","date":"2013","source":"European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery","url":"https://pubmed.ncbi.nlm.nih.gov/24013453","citation_count":15,"is_preprint":false},{"pmid":"31318581","id":"PMC_31318581","title":"IL-17C Protects Nasal Epithelium from Pseudomonas aeruginosa Infection.","date":"2020","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/31318581","citation_count":13,"is_preprint":false},{"pmid":"26547017","id":"PMC_26547017","title":"Th17 master transcription factors RORα and RORγ regulate the expression of IL-17C, IL-17D and IL-17F in Cynoglossus semilaevis.","date":"2015","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26547017","citation_count":13,"is_preprint":false},{"pmid":"38704381","id":"PMC_38704381","title":"IL-17C is a driver of damaging inflammation during Neisseria gonorrhoeae infection of human Fallopian tube.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38704381","citation_count":12,"is_preprint":false},{"pmid":"36865346","id":"PMC_36865346","title":"Aldehyde Dehydrogenase 2 Protects the Kidney from Ischemia-Reperfusion Injury by Suppressing the IκBα/NF-κB/IL-17C Pathway.","date":"2023","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/36865346","citation_count":12,"is_preprint":false},{"pmid":"23354891","id":"PMC_23354891","title":"Primary mucosal melanoma arising from the eustachian tube with CTLA-4, IL-17A, IL-17C, and IL-17E upregulation.","date":"2013","source":"Ear, nose, & throat journal","url":"https://pubmed.ncbi.nlm.nih.gov/23354891","citation_count":11,"is_preprint":false},{"pmid":"36130829","id":"PMC_36130829","title":"Th17-Derived Cytokines Synergistically Enhance IL-17C Production by the Colonic Epithelium.","date":"2022","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/36130829","citation_count":10,"is_preprint":false},{"pmid":"39568050","id":"PMC_39568050","title":"Contribution of IL-17C-mediated macrophage polarization to Type 17 inflammation in neutrophilic asthma.","date":"2024","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/39568050","citation_count":9,"is_preprint":false},{"pmid":"30534126","id":"PMC_30534126","title":"IL-17C Mitigates Murine Acute Graft-vs.-Host Disease by Promoting Intestinal Barrier Functions and Treg Differentiation.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30534126","citation_count":9,"is_preprint":false},{"pmid":"34576717","id":"PMC_34576717","title":"IL-17C and IL-17RE Promote Wound Closure in a Staphylococcus aureus-Based Murine Wound Infection Model.","date":"2021","source":"Microorganisms","url":"https://pubmed.ncbi.nlm.nih.gov/34576717","citation_count":8,"is_preprint":false},{"pmid":"34428552","id":"PMC_34428552","title":"Molecular characterization of fish cytokine IL-17C from Amphiprion clarkii and its immunomodulatory effects on the responses to pathogen-associated molecular patterns and bacterial challenges.","date":"2021","source":"Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/34428552","citation_count":8,"is_preprint":false},{"pmid":"37480587","id":"PMC_37480587","title":"PepScaf: Harnessing Machine Learning with In Vitro Selection toward De Novo Macrocyclic Peptides against IL-17C/IL-17RE Interaction.","date":"2023","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37480587","citation_count":7,"is_preprint":false},{"pmid":"40954243","id":"PMC_40954243","title":"PPARγ accelerates OSCC progression via Th17 polarization and CEBPA/IL-17C signaling.","date":"2025","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40954243","citation_count":3,"is_preprint":false},{"pmid":"37173646","id":"PMC_37173646","title":"Nonnegative matrix factorization analysis and multiple machine learning methods identified IL17C and ACOXL as novel diagnostic biomarkers for atherosclerosis.","date":"2023","source":"BMC bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/37173646","citation_count":3,"is_preprint":false},{"pmid":"40244332","id":"PMC_40244332","title":"IL-17C-Mediated Upregulation of SMURF2 Induces Psoriatic Changes in Keratinocytes by Facilitating PPP6C Ubiquitination.","date":"2025","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/40244332","citation_count":2,"is_preprint":false},{"pmid":"40986185","id":"PMC_40986185","title":"IL-17C as a Driver of Inflammation in Psoriasis.","date":"2025","source":"Advances in therapy","url":"https://pubmed.ncbi.nlm.nih.gov/40986185","citation_count":1,"is_preprint":false},{"pmid":"33162788","id":"PMC_33162788","title":"IL-17C expression and its correlation with pediatric adenoids: a preliminary study.","date":"2020","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33162788","citation_count":1,"is_preprint":false},{"pmid":"34796039","id":"PMC_34796039","title":"IL-17 and IL-17C Signaling Protects the Intestinal Epithelium against Diisopropyl Fluorophosphate Exposure in an Acute Model of Gulf War Veterans' Illnesses.","date":"2021","source":"Immune network","url":"https://pubmed.ncbi.nlm.nih.gov/34796039","citation_count":1,"is_preprint":false},{"pmid":"40637095","id":"PMC_40637095","title":"Cyprinid Herpesvirus 2 Infection Activates IL-17C/NF-κB/IFNγ Antiviral Signalling Axis in Caudal Fin Cells of Carassius auratus Gibelio.","date":"2025","source":"Journal of fish diseases","url":"https://pubmed.ncbi.nlm.nih.gov/40637095","citation_count":1,"is_preprint":false},{"pmid":"40974979","id":"PMC_40974979","title":"The protective role of IL-17C in oral squamous cell carcinoma.","date":"2025","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40974979","citation_count":0,"is_preprint":false},{"pmid":"41620554","id":"PMC_41620554","title":"Synovial macrophage rhoa protects against osteoarthritis by suppressing YAP/IL-17C mediated chondrocyte senescence.","date":"2026","source":"Cell biology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/41620554","citation_count":0,"is_preprint":false},{"pmid":"38246174","id":"PMC_38246174","title":"[MOR106 alleviates inflammation in mice with atopic dermatitis by blocking the JAK2/STAT3 signaling pathway and inhibiting IL-17C-mediated Tfh cell differentiation].","date":"2024","source":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38246174","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.12.25335624","title":"Multi-Omics Molecular Profiling Enables Rapid Diagnosis of Erythrodermic Skin Diseases","date":"2025-09-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.12.25335624","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.29.605666","title":"Effects of two different compounds on seizure suppression using the zebrafish PTZ-seizure model","date":"2024-07-30","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.29.605666","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.09.24315196","title":"Distinct proteomic signatures in Ethiopians predict acute and long-term sequelae of COVID-19","date":"2024-10-10","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.09.24315196","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":37029,"output_tokens":9161,"usd":0.124251,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19495,"output_tokens":5104,"usd":0.112537,"stage2_stop_reason":"end_turn"},"total_usd":0.236788,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"IL-17C was cloned and shown to stimulate release of TNF-α and IL-1β from the monocytic cell line THP-1, and to bind THP-1 cells by FACS analysis. IL-17C does not bind the human IL-17 receptor extracellular domain and does not induce IL-6 from fibroblasts, distinguishing it from IL-17A.\",\n      \"method\": \"Recombinant protein expression, cytokine release assay (ELISA), FACS binding assay, IL-17 receptor binding assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and functional assays in cell lines, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"10639155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-17C signals through a heterodimeric receptor complex composed of IL-17RA and IL-17RE, which is preferentially expressed on tissue epithelial cells. IL-17C acts in an autocrine manner on epithelial cells to stimulate proinflammatory cytokines, chemokines, and antimicrobial peptides. IL-17C promoted inflammation in imiquimod-induced skin inflammation but exerted protective functions in DSS-induced colitis.\",\n      \"method\": \"Receptor binding assays, gene expression analysis, knockout mouse models (imiquimod and DSS colitis models), co-immunoprecipitation of receptor complex\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated across two independent simultaneous publications, receptor complex identification, in vivo knockout models with defined phenotypes\",\n      \"pmids\": [\"21993848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-17RE is the specific functional receptor for IL-17C. IL-17C signals through the IL-17RE–IL-17RA heterodimeric complex to induce antibacterial peptides and proinflammatory molecules in colon epithelial cells. IL-17C is upregulated in colon epithelial cells during Citrobacter rodentium infection, acts synergistically with IL-22 to induce antibacterial peptides, and loss of IL-17RE leads to greater bacterial burden and early mortality.\",\n      \"method\": \"Receptor identification (IL-17RE as orphan receptor for IL-17C), IL-17RE-deficient mouse model, infection model with C. rodentium, gene expression assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor identification validated with genetic knockout and in vivo infection model, replicated independently in same year\",\n      \"pmids\": [\"21993849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IL-17C is required for regulation of acute experimental colitis (DSS model); IL-17C-deficient mice show exacerbated disease with increased IL-17 expression by γδ T cells and Th17 cells. IL-17C directly regulates the expression of the tight junction molecule occludin by colonic epithelial cells.\",\n      \"method\": \"IL-17C-deficient mouse model, DSS colitis model, gene expression analysis, tight junction protein assessment\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined cellular and molecular phenotype, multiple orthogonal readouts\",\n      \"pmids\": [\"23024280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NOD2 activation in keratinocytes mediates Staphylococcus aureus-induced IL-17C expression via the first NF-κB binding site in the IL-17C promoter. Crohn's disease-associated NOD2 mutations (3020insC, R702W) significantly reduced NOD2-mediated IL-17C induction. IL-17C knockdown increased S. aureus survival in keratinocytes.\",\n      \"method\": \"NOD2 overexpression in HEK293 cells, IL-17C promoter reporter assay, siRNA knockdown, S. aureus infection of primary keratinocytes\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — promoter reporter assay with mutagenesis/variant analysis plus siRNA knockdown with functional bacterial survival readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23892590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Keratinocyte overexpression of IL-17C drives psoriasiform skin inflammation in mice; involved skin shows epidermal hyperplasia, angiogenesis, leukocyte infiltration, and upregulation of TNF-α, IL-1α/β, IL-17A/F, IL-23p19. IL-17C and TNF-α together produce similar inflammatory gene responses in keratinocytes as IL-17A/TNF-α, indicating a positive proinflammatory feedback loop. TNF-α inhibition ameliorated the phenotype.\",\n      \"method\": \"Transgenic mouse model (keratinocyte-specific IL-17C overexpression), cytokine stimulation of primary keratinocytes, TNF-α inhibitor treatment\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic overexpression model with detailed phenotypic and molecular characterization plus pharmacological intervention, single lab\",\n      \"pmids\": [\"23359500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL-17C is expressed by human bronchial epithelial cells (HBECs) in response to bacterial pathogens (Pseudomonas aeruginosa, Haemophilus influenzae) and TLR3/TLR5 ligands. IL-17C enhanced inflammatory responses of respiratory epithelial cells; cigarette smoke suppressed IL-17C expression in response to bacterial infection.\",\n      \"method\": \"In vitro bacterial infection of HBECs, TLR ligand stimulation, gene expression analysis, in vivo mouse colonization model\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo experiments, single lab, multiple stimuli tested\",\n      \"pmids\": [\"23221046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In human IBD, IL-17C production in intestinal epithelial cells is regulated by TNF-α through NF-κB, ERK1/2, and p38 pathways, and by IL-17A through Akt, MCPIP1 (Regnase-1), and C/EBPδ pathways. IL-17A strongly amplifies TNF-α-induced IL-17C production in enteroendocrine and goblet cells. IL-17C upregulates the Th17 chemoattractant CCL20 in IECs.\",\n      \"method\": \"Primary IEC stimulation, signaling pathway inhibitors, qPCR, immunoblotting, ELISA, immunohistochemistry of IBD patient tissue\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with multiple signaling inhibitors, single lab\",\n      \"pmids\": [\"25492478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-17C expression in airway bronchial epithelial cells is induced by polyI:C via the TLR3–TRIF–NF-κB pathway. IL-17C acts in an autocrine/paracrine manner through IL-17RE to enhance expression of antimicrobial peptides (hBD2) and proinflammatory mediators (CSF3, S100A12). Knockdown of IL-17RE attenuated polyI:C-induced hBD2, CSF3, and S100A12 expression without reducing IL-17C itself.\",\n      \"method\": \"Primary normal human bronchial epithelial (NHBE) cell stimulation, pathway inhibitors (Pepinh-TRIF, BAY11, NF-κB p65 siRNA), IL-17RE siRNA knockdown, IL-17C siRNA knockdown\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal siRNA knockdowns, pharmacological inhibition, and pathway dissection in primary cells, single lab\",\n      \"pmids\": [\"23944933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-36γ induces IL-17C expression in keratinocytes and IL-17C reciprocally sustains a proinflammatory self-amplifying loop with IL-36γ. IL-17C affects keratinocyte defensin gene expression only in combination with TNF-α (not alone). Both IL-36γ and IL-17C are elevated in anti-TNF-induced psoriasiform skin lesions of Crohn's disease patients and their expression levels are strongly correlated.\",\n      \"method\": \"Primary keratinocyte stimulation, qRT-PCR, immunoblotting, ELISA, immunohistochemistry of patient skin biopsies\",\n      \"journal\": \"Inflammatory bowel diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, in vitro experiments with patient tissue correlation, multiple methods\",\n      \"pmids\": [\"25299544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-17C is required for lethal inflammation during systemic fungal (Candida) infection; IL-17C-deficient mice show increased survival and attenuated kidney tissue damage with decreased pro-inflammatory cytokine expression despite similar fungal loads. IL-17C directly acts on renal epithelial cells in vitro to promote pro-inflammatory cytokine production.\",\n      \"method\": \"IL-17C-deficient mouse model, systemic fungal infection model, in vitro renal epithelial cell stimulation, cytokine measurement\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with in vivo and in vitro validation, single lab\",\n      \"pmids\": [\"26166766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MCPIP1 (Regnase-1) is a negative regulator of IL-17C signaling in non-hematopoietic (epithelial) cells. MCPIP1-deficient keratinocytes show increased responsiveness to IL-17A and IL-17C stimulation. Epistasis analysis (Zc3h12a+/-Il17c-/- double mice) demonstrated that pathology in MCPIP1-deficient mice is partly dependent on IL-17C.\",\n      \"method\": \"MCPIP1 (Zc3h12a) heterozygous knockout mice, radiation bone marrow chimeras, double-knockout epistasis (Zc3h12a+/-Il17c-/-), primary keratinocyte stimulation with IL-17C\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double knockouts, bone marrow chimeras, and primary cell experiments, multiple orthogonal methods\",\n      \"pmids\": [\"27920272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-17A-mediated upregulation of epithelial IL-17C amplifies chemokine (KC, MIP-2) production and neutrophil recruitment in acute P. aeruginosa pneumonia. IL-17C-deficient mice show decreased neutrophil numbers and chemokine expression. IL-17A stimulation of primary alveolar epithelial cells directly increases IL-17C expression in vitro.\",\n      \"method\": \"IL-17C-/- and IL-17A-/- mouse models, P. aeruginosa lung infection model, primary alveolar epithelial cell stimulation, cytokine/chemokine measurement\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two genetic knockout strains with in vitro mechanistic validation, single lab\",\n      \"pmids\": [\"27694471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-17C/IL-17RE axis promotes TH17 cell-driven autoimmune hepatitis. IL-17C is produced by hepatocytes, and IL-17RE is expressed on liver-resident T cells. Mechanistically, IL-17C augments IL-2 expression by intrahepatic CD4+ T cells to promote NK cell activation and liver damage.\",\n      \"method\": \"IL-17C and IL-17RE knockout mouse models (Con A hepatitis model), human patient liver samples, in vitro T cell stimulation, cytokine measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two genetic knockouts with mechanistic pathway (IL-2/NK axis), single lab\",\n      \"pmids\": [\"27956525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-17C expression in airway epithelial cells is induced by NTHi (nontypeable Haemophilus influenzae) through TLR-2/4 signaling. IL-17C promotes neutrophil recruitment into tumors by increasing neutrophil chemokine (KC, MIP-2) expression in lung cancer cells, thereby enhancing tumor growth in a metastatic model.\",\n      \"method\": \"IL-17C-/- and TLR-2/4-/- mouse models, metastatic lung cancer model with NTHi, in vitro cytokine stimulation of lung cancer cells, neutrophil chemokine measurement\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two genetic knockouts with in vitro mechanistic validation, single lab\",\n      \"pmids\": [\"28346430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Keratinocytes produce IL-17C during HSV-2 reactivation. IL-17RE (the IL-17C-specific receptor) is expressed on nerve fibers in human skin and sensory neurons in dorsal root ganglia. Exogenous IL-17C provided directional guidance and promoted neurite growth and branching in microfluidic devices, and IL-17C pretreatment reduced apoptosis in HSV-2-infected primary neurons.\",\n      \"method\": \"Human skin biopsy analysis, ex vivo microfluidic neurite growth assay, primary neuron apoptosis assay with recombinant IL-17C, immunostaining of human skin and DRG\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal experiments (neurite growth, apoptosis, receptor localization), single lab\",\n      \"pmids\": [\"28663436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-13 negatively regulates IL-1β-induced IL-17C expression in airway epithelial cells by suppressing NF-κB-mediated transcriptional activation. IL-1β induces IL-17C through NF-κB (p65 binds IL-17C promoter at -130/-120 and -157/-147 sites); IL-13 activates JAK/STAT6 signaling to reduce p65 binding to the IL-17C promoter without affecting upstream IκBα/NF-κB activation.\",\n      \"method\": \"Primary NHBE cell stimulation, NF-κB p65 siRNA, STAT6 siRNA, JAK inhibitor (ruxolitinib), chromatin immunoprecipitation (ChIP) of IL-17C promoter, Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP analysis of IL-17C promoter binding plus siRNA knockdowns and pharmacological inhibition, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"29203240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-17C/IL-17RE signaling on CD4+ TH17 cells promotes TH17-driven glomerular inflammation. IL-17RE is highly expressed by CD4+ TH17 cells; loss of IL-17RE specifically prevents TH17 responses and subsequent tissue injury. Bone marrow transplantation experiments showed IL-17C is produced by tissue-resident (non-lymphocyte) cells.\",\n      \"method\": \"IL-17C-/- and IL-17RE-/- mouse models of crescentic GN and lupus nephritis, bone marrow transplantation chimeras, TH17 response assessment, human patient serum IL-17C measurement\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two genetic knockouts, bone marrow chimera experiments, two independent disease models, single lab\",\n      \"pmids\": [\"29483158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Anti-IL-17C antibody MOR106 selectively binds human and mouse IL-17C and inhibits IL-17C binding to its IL-17RE receptor. MOR106 suppressed skin inflammation in IL-23-induced psoriatic and calcipotriol-induced AD mouse models, reducing T cells, neutrophils, eosinophils, TSLP, IL-33, IgE, and mast cell numbers.\",\n      \"method\": \"Neutralizing antibody generation and characterization, in vivo IL-23-induced psoriasis model, calcipotriol AD model, flaky tail mouse model, cytokine/immune cell measurements\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody-based receptor blocking with multiple in vivo models, single lab\",\n      \"pmids\": [\"29474945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HRV-bacterial coinfection synergistically induces IL-17C expression in bronchial epithelial cells via NF-κB and p38 MAPK signaling. IL-17C induces CXCL1 release from epithelial cells, and IL-17C knockdown significantly reduces CXCL1 induction and neutrophil chemotaxis.\",\n      \"method\": \"Primary bronchial epithelial cell infection with HRV and bacteria, pharmacological inhibitors (NF-κB, p38 MAPK), IL-17C siRNA knockdown, CXCL1 ELISA, neutrophil chemotaxis assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway inhibitors plus siRNA with functional neutrophil chemotaxis readout, single lab\",\n      \"pmids\": [\"30504421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TLR5 signaling mediates F4+ ETEC-induced IL-17C expression in porcine intestinal epithelial cells. Both ETEC infection and exogenous IL-17C increased expression of antimicrobial peptides (pBD-2) and tight junction proteins (claudin-1, claudin-2, occludin), demonstrating an autocrine/paracrine epithelial defense function.\",\n      \"method\": \"Porcine IPEC-J2 cell infection model, TLR5 signaling analysis, recombinant IL-17C stimulation, gene expression assay\",\n      \"journal\": \"Veterinary research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro pathway analysis with exogenous protein stimulation, single lab\",\n      \"pmids\": [\"31221216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17C/IL-17RE axis promotes neutrophil recruitment during acute S. pneumoniae pneumonia. IL-17RE-deficient mice showed decreased pulmonary neutrophil numbers, decreased G-CSF and TNF-α, and reduced granulocyte-monocyte progenitor (GMP) fractions. IL-17C-deficient mice also showed reduced neutrophil numbers at 24h post-infection.\",\n      \"method\": \"IL-17RE-/- and IL-17C-/- mouse models, S. pneumoniae lung infection, flow cytometry of immune cells and bone marrow progenitors, cytokine measurement\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two genetic knockouts with defined cellular phenotype, single lab\",\n      \"pmids\": [\"31481409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Replication-dependent rhinovirus infection drives basolateral (but not apical) IL-17C protein release from differentiated airway epithelial cells. Columnar epithelial cells express more IL-17C than basal cells. Basolateral IL-17C acts in an autocrine/paracrine manner to promote basolateral CXCL1 production.\",\n      \"method\": \"Highly differentiated human bronchial epithelial (HBE) cell air-liquid interface cultures, apical HRV infection, viral replication inhibitor, separated apical/basolateral secretion analysis, enriched cell population analysis\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — well-differentiated air-liquid interface model, multiple controls, directional secretion analysis, single lab\",\n      \"pmids\": [\"32232015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-17C has a pathogenic role in kidney ischemia/reperfusion injury. IL-17C is upregulated in hypoxic kidney tubular epithelial cells. Neutralizing IL-17C antibody or IL-17RE knockout attenuated tubular injury, oxidative stress, inflammation, TH17 activation, IL-17A expression, and downstream TNF-α and IL-1β. IL-17C knockdown with siRNA decreased hypoxia-induced inflammation in kidney tubular cells, and silencing IL-17RE abrogated IL-17C effects.\",\n      \"method\": \"IL-17RE-/- mouse model, neutralizing antibody treatment, siRNA knockdown in kidney tubular cells, kidney IRI model, cytokine and oxidative stress measurements\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout plus neutralizing antibody plus siRNA knockdown with multiple orthogonal mechanistic readouts, multiple approaches converging\",\n      \"pmids\": [\"32331702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-17C promotes tumor angiogenesis in colorectal cancer by inducing VEGF production via a STAT3/miR-23a-3p/SEMA6D axis. IL-17C activates STAT3 to increase miR-23a-3p expression, which suppresses SEMA6D to permit VEGF production. IL-17C-induced angiogenesis was blocked by VEGFR2 inhibitor Ki8751 in xenograft experiments.\",\n      \"method\": \"In vitro angiogenesis assay, mouse xenograft model, ELISA, siRNA gene silencing, VEGFR2 inhibitor treatment, immunostaining\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — xenograft model with pharmacological inhibition and gene silencing, single lab\",\n      \"pmids\": [\"32492770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-17C amplifies epithelial inflammation through autocrine induction of IL-17C itself in keratinocytes, and promotes expression of innate cytokines, antimicrobial peptides (IL-36G, S100A7, HBD2) and chemokines (CXCL8, CXCL10, CCL5, VEGF). IL-17C depletion with anti-IL-17C antibody MOR106 significantly reduced T cells, neutrophils, and eosinophils in mouse psoriasis and AD models and downregulated inflammatory mediators in human skin explants.\",\n      \"method\": \"Primary human keratinocyte stimulation, neutralizing antibody MOR106, IL-23 psoriasis and MC903 AD mouse models, flow cytometry, human skin ex vivo explant cultures, neutrophil migration assay\",\n      \"journal\": \"Journal of the European Academy of Dermatology and Venereology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vivo models and human ex vivo confirmation, single lab\",\n      \"pmids\": [\"31793105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Th17-derived cytokines TNF-α, IL-17A, and IL-22 synergistically enhance IL-17C expression in colonic epithelial cells. TNF-α acts through NF-κB (blocked by IκBα inhibitor), while IL-17A and IL-22 act through AP-1 in a p38 MAPK-dependent manner to amplify IL-17C expression, establishing an inflammatory amplification loop between epithelial cells and Th17 cells.\",\n      \"method\": \"Human colonic epithelial cell lines and primary colonic organoids, cytokine stimulation, pharmacological NF-κB and p38 MAPK inhibitors, qPCR\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection in primary organoids plus cell lines, single lab\",\n      \"pmids\": [\"36130829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LL37 activates TLR8 in keratinocytes and induces IL-17C through the induction of IL-36γ. IL-36 receptor antagonistic antibody suppressed IL-17C induced by LL37, placing IL-36γ upstream of IL-17C induction in this pathway. IL-17C was not altered by blockade of TLR7/8 directly, indicating LL37 acts on IL-17C indirectly through IL-36γ.\",\n      \"method\": \"Primary keratinocyte stimulation with LL37, TLR7/8 inhibitors, IL-36 receptor antagonist antibody, psoriatic skin immunostaining, gene expression analysis\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological inhibition pathway dissection, single lab, defines upstream regulators\",\n      \"pmids\": [\"36496195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Hypoxia-induced IL-17C upregulation in kidney tubular cells is predominantly mediated by the NF-κB pathway (IκBα/NF-κB p65 phosphorylation). ALDH2 deficiency increases NF-κB phosphorylation, leading to increased IL-17C expression during kidney IRI. NF-κB inhibition in HK-2 cells prevented the ALDH2-knockdown-induced increase in IL-17C.\",\n      \"method\": \"ALDH2-/- mouse model, kidney IRI, RNA-seq, PCR, Western blot, HK-2 cell hypoxia/reoxygenation model, ALDH2 siRNA knockdown, NF-κB inhibitor\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout plus siRNA plus pharmacological inhibition with pathway validation, single lab\",\n      \"pmids\": [\"36865346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Delayed (post-ischemia) IL-17C neutralization has reno-protective effects on kidney IRI. IL-17C blockade attenuated diabetic nephropathy (DN), including albuminuria, mesangial matrix accumulation, and podocyte loss. Mechanistic studies showed that hypoxia or high glucose-induced IL-17C upregulation is predominantly mediated by the NF-κB pathway, and IL-17C neutralization repressed downstream pro-inflammatory cytokines and Th17/IL-17A activation.\",\n      \"method\": \"IL-17C neutralizing antibody treatment in mouse IRI and db/db diabetic nephropathy models, NF-κB p65 siRNA knockdown, HIF-1α inhibitor (YC-1), kidney function/histology assessment, cytokine measurement\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — neutralizing antibody and siRNA mechanistic validation in two disease models, single lab\",\n      \"pmids\": [\"37263138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-17C is highly induced in human Fallopian tube epithelium during N. gonorrhoeae infection. Human Fallopian tubes express the IL-17C receptor on the epithelial surface. Treatment of Fallopian tube explants with purified IL-17C induces pro-inflammatory cytokine secretion and causes sloughing of the epithelium and generalized tissue damage.\",\n      \"method\": \"Human Fallopian tube ex vivo culture with N. gonorrhoeae, RNA sequencing, purified IL-17C treatment, receptor expression analysis, histological assessment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human ex vivo model with RNA-seq, receptor localization, and purified cytokine functional assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38704381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-17C promotes M1 macrophage polarization in neutrophilic asthma via IL-17RE. In vitro, IL-17C synergizes with IFN-γ to activate STAT1 in IL-17RE-overexpressing macrophages (Raw264.7), upregulating M1-related genes, while inhibiting IL-4-induced STAT6 activation and M2 differentiation. In vivo, deficiency of IL-17C reversed pro-inflammatory phenotypes and inhibited M1 macrophage expansion.\",\n      \"method\": \"IL-17c-/- mouse model, OVA/CFA asthma model, exogenous rmIL-17C administration, IL-17RE-overexpressing Raw264.7 cells, flow cytometry, Western blot for STAT1/STAT6\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with in vitro receptor-overexpression mechanistic validation, single lab\",\n      \"pmids\": [\"39568050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-17C upregulates SMURF2 expression in keratinocytes, leading to psoriasis-like changes. SMURF2 interacts with PPP6C (by co-immunoprecipitation) and promotes its ubiquitination and degradation. Silencing SMURF2 inhibited the effects of IL-17C on keratinocytes, and SMURF2 overexpression enhanced IL-17C effects by targeting PPP6C for degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown of SMURF2, lentiviral overexpression, imiquimod psoriasis mouse model, HaCaT cell stimulation with IL-17C, Western blot, flow cytometry\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-immunoprecipitation and ubiquitination assay with siRNA and overexpression validation, single lab\",\n      \"pmids\": [\"40244332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Macrophage RhoA ablation leads to activation of Hippo pathway effectors YAP/CCN2, causing IL-17C transcription independently of the canonical ROCK pathway. IL-17C secreted by RhoA-deficient macrophages induces chondrocyte senescence (increased p53/p21, ROS, mitochondrial dysfunction, suppressed autophagy) via activation of the PI3K/AKT/mTOR pathway.\",\n      \"method\": \"Macrophage-specific RhoA conditional knockout mouse model, OA mouse model, transcriptome sequencing, Western blot, immunofluorescence, ELISA, YAP/CCN2 pathway analysis\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific conditional knockout with transcriptomic and mechanistic pathway validation, single lab\",\n      \"pmids\": [\"41620554\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-17C is an epithelial-derived homodimeric cytokine that signals through a heterodimeric IL-17RA/IL-17RE receptor complex to act in an autocrine/paracrine manner on epithelial cells, promoting innate immune responses including antimicrobial peptide production, tight junction maintenance, and proinflammatory cytokine/chemokine expression; its expression is induced by bacterial and viral pathogens via TLR–NF-κB and related pathways, amplified by Th17 cytokines (TNF-α, IL-17A, IL-22) and IL-36γ, and negatively regulated by MCPIP1/Regnase-1 and IL-13/STAT6 signaling; beyond the epithelium, IL-17C also signals through IL-17RE on CD4+ TH17 cells to amplify adaptive TH17 responses, and its downstream effects in various tissues involve NF-κB-mediated cytokine induction, neutrophil recruitment via CXCL1/KC/MIP-2, and in specific contexts, STAT3/miR-23a-3p/SEMA6D-driven angiogenesis and SMURF2-mediated PPP6C ubiquitination.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL-17C is an epithelial-derived cytokine that drives innate and adaptive inflammatory responses by signaling through a heterodimeric IL-17RA/IL-17RE receptor complex preferentially expressed on tissue epithelial cells, acting in an autocrine/paracrine fashion to induce proinflammatory cytokines, chemokines, and antimicrobial peptides [#1, #2]. Functionally distinct from IL-17A, it was originally identified as a cytokine that stimulates TNF-\\u03b1 and IL-1\\u03b2 release from monocytic cells and does not bind the IL-17A receptor [#0]. At barrier surfaces it is induced by bacterial and viral pathogens through pattern-recognition and NF-\\u03baB signaling \\u2014 NOD2 in keratinocytes responding to S. aureus [#4], TLR3-TRIF-NF-\\u03baB and TLR2/4/5 routes in airway and intestinal epithelium [#8, #14], and NF-\\u03baB/p38 MAPK during viral-bacterial coinfection [#19] \\u2014 and reinforces epithelial defense by inducing antimicrobial peptides and maintaining tight-junction proteins such as occludin [#3, #20]. IL-17C participates in self-amplifying inflammatory loops: it is upregulated by Th17 cytokines (TNF-\\u03b1, IL-17A, IL-22) acting via NF-\\u03baB and AP-1/p38 [#26], reciprocally sustained by IL-36\\u03b3 [#9, #27], and negatively regulated by MCPIP1/Regnase-1 [#11] and by IL-13/STAT6 signaling that reduces NF-\\u03baB p65 binding to the IL-17C promoter [#16]. Through IL-17RE on CD4+ TH17 cells it amplifies adaptive TH17-driven tissue injury [#17], and its downstream effects span neutrophil recruitment via CXCL1/KC/MIP-2 [#12, #19], M1 macrophage polarization through STAT1 [#31], and tumor angiogenesis via a STAT3/miR-23a-3p/SEMA6D axis [#24]. These activities give IL-17C dual protective and pathogenic roles across infection, psoriasis, colitis, nephropathy, and cancer [#2, #5, #23], making it a therapeutic target addressed by neutralizing antibodies [#18, #25].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established IL-17C as a distinct cytokine by showing it induces TNF-\\u03b1 and IL-1\\u03b2 from monocytic cells yet, unlike IL-17A, does not bind the IL-17 receptor or induce fibroblast IL-6.\",\n      \"evidence\": \"Recombinant protein cytokine-release assays, FACS binding, and IL-17 receptor binding assays in cell lines\",\n      \"pmids\": [\"10639155\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not identify the functional receptor\", \"Cellular source and physiological context unaddressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the IL-17C receptor as the IL-17RA/IL-17RE heterodimer on epithelial cells, answering how IL-17C signals and revealing an autocrine epithelial innate-immune function with context-dependent protective and pathogenic roles.\",\n      \"evidence\": \"Receptor binding and co-IP, IL-17RE-deficient mice, imiquimod skin and DSS colitis and C. rodentium infection models\",\n      \"pmids\": [\"21993848\", \"21993849\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of receptor engagement not resolved\", \"Downstream signaling components downstream of IL-17RE not fully mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed IL-17C maintains epithelial barrier integrity by directly regulating the tight-junction protein occludin, linking it to protection in acute colitis.\",\n      \"evidence\": \"IL-17C-deficient mice in DSS colitis with tight-junction protein assessment\",\n      \"pmids\": [\"23024280\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct mechanism of occludin regulation not defined\", \"Relationship between barrier and inflammatory functions unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified pathogen-sensing routes (NOD2, TLR3/5) that induce epithelial IL-17C and demonstrated its requirement for antibacterial defense and for driving psoriasiform skin inflammation.\",\n      \"evidence\": \"NOD2 promoter reporter and variant analysis, siRNA knockdown with S. aureus survival, keratinocyte-specific transgenic overexpression, HBEC infection\",\n      \"pmids\": [\"23892590\", \"23359500\", \"23221046\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Relative contribution of distinct PRR pathways across tissues unclear\", \"Why the same cytokine is protective vs pathogenic not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped upstream induction and amplification of IL-17C, showing NF-\\u03baB-driven transcription via TLR3-TRIF, Th17-cytokine amplification, and IL-36\\u03b3 reciprocal loops, and CCL20-mediated TH17 chemoattraction.\",\n      \"evidence\": \"Primary NHBE/IEC/keratinocyte stimulation with siRNA, pathway inhibitors, ELISA, patient tissue immunohistochemistry\",\n      \"pmids\": [\"25492478\", \"23944933\", \"25299544\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Quantitative hierarchy among inducers not established\", \"In vivo relevance of the IL-36\\u03b3 loop incompletely defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated a pathogenic role for IL-17C in lethal systemic Candida infection through direct action on renal epithelial cells, dissociating immunopathology from fungal clearance.\",\n      \"evidence\": \"IL-17C-deficient mice in systemic fungal infection with in vitro renal epithelial stimulation\",\n      \"pmids\": [\"26166766\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Receptor dependence in this model not directly tested\", \"Specific renal cell mediators not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined negative regulation by MCPIP1/Regnase-1 and showed IL-17C amplifies neutrophilic chemokine responses during bacterial pneumonia and TH17-driven hepatitis.\",\n      \"evidence\": \"Zc3h12a/Il17c epistasis double knockouts, bone marrow chimeras, IL-17C-/- and IL-17A-/- pneumonia models, Con A hepatitis models\",\n      \"pmids\": [\"27920272\", \"27694471\", \"27956525\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular target of MCPIP1 within the IL-17C axis not specified\", \"Tissue-specific balance of regulators unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended IL-17C signaling beyond epithelium to neurons and tumor settings, showing IL-17RE on sensory neurons mediates neurite guidance and IL-17C promotes tumor-associated neutrophil recruitment.\",\n      \"evidence\": \"Microfluidic neurite assays, neuron apoptosis assays, IL-17C-/- and TLR2/4-/- metastatic lung cancer models, immunostaining\",\n      \"pmids\": [\"28663436\", \"28346430\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Neuronal signaling downstream of IL-17RE undefined\", \"Direct vs indirect tumor-promoting mechanisms not separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed IL-17RE on CD4+ TH17 cells directly amplifies adaptive TH17 responses and established IL-17C neutralization (MOR106) as therapeutically effective in skin inflammation models.\",\n      \"evidence\": \"IL-17C-/- and IL-17RE-/- glomerulonephritis/lupus models, bone marrow chimeras, neutralizing antibody in psoriasis and AD models\",\n      \"pmids\": [\"29483158\", \"29474945\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Intracellular signaling in TH17 cells downstream of IL-17RE not mapped\", \"Durability and specificity of antibody effects in humans not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified IL-13/STAT6 as a negative regulator that suppresses NF-\\u03baB p65 binding to the IL-17C promoter without affecting upstream NF-\\u03baB activation.\",\n      \"evidence\": \"ChIP of IL-17C promoter, p65/STAT6 siRNA, JAK inhibition in primary NHBE cells\",\n      \"pmids\": [\"29203240\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism by which STAT6 blocks p65 recruitment not defined\", \"In vivo relevance in Th2 disease not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Consolidated IL-17C as a pathogenic driver in kidney injury and uncovered effector mechanisms including STAT3/miR-23a-3p/SEMA6D-driven tumor angiogenesis and directional basolateral epithelial secretion.\",\n      \"evidence\": \"IL-17RE-/- mice, neutralizing antibody, siRNA in tubular cells, kidney IRI models, CRC xenograft angiogenesis assays, air-liquid interface HBE cultures\",\n      \"pmids\": [\"32331702\", \"32492770\", \"32232015\", \"31793105\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Receptor-proximal signaling driving STAT3 activation not defined\", \"Determinants of polarized secretion unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Detailed NF-\\u03baB as the predominant transcriptional driver of hypoxia/high-glucose-induced renal IL-17C and validated delayed IL-17C neutralization as reno-protective across IRI and diabetic nephropathy.\",\n      \"evidence\": \"ALDH2-/- mice, HK-2 hypoxia model, NF-\\u03baB and HIF-1\\u03b1 inhibitors, p65 siRNA, neutralizing antibody in IRI and db/db models\",\n      \"pmids\": [\"36865346\", \"37263138\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Link between ALDH2 deficiency and NF-\\u03baB activation incompletely defined\", \"Translational therapeutic window in human kidney disease unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded the cellular targets of IL-17C to macrophages, showing STAT1-driven M1 polarization via IL-17RE, and demonstrated direct epithelial damage in human Fallopian tube during gonococcal infection.\",\n      \"evidence\": \"IL-17c-/- asthma model, IL-17RE-overexpressing macrophages with STAT1/STAT6 analysis, human Fallopian tube explants with N. gonorrhoeae and purified IL-17C, RNA-seq\",\n      \"pmids\": [\"39568050\", \"38704381\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How a single receptor produces distinct STAT1 vs STAT3 outputs unresolved\", \"Mechanism of IL-17C-induced epithelial sloughing undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified intracellular effector consequences of IL-17C signaling, including SMURF2 upregulation driving PPP6C ubiquitination in keratinocytes and YAP/CCN2- and PI3K/AKT/mTOR-linked induction and effects in macrophage/chondrocyte contexts.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, siRNA/overexpression in HaCaT and imiquimod psoriasis; macrophage RhoA conditional knockout with transcriptomics in OA model\",\n      \"pmids\": [\"40244332\", \"41620554\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single Co-IP for SMURF2-PPP6C without reciprocal/structural validation\", \"How IL-17C links receptor engagement to SMURF2 transcription unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The receptor-proximal signaling cascade that converts IL-17RA/IL-17RE engagement into distinct outputs (STAT1 vs STAT3 vs NF-\\u03baB) and the structural basis of ligand-receptor recognition remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of the IL-17C/IL-17RA/IL-17RE complex\", \"Adaptor and kinase intermediates downstream of IL-17RE not defined\", \"Determinants of protective vs pathogenic outcomes not mechanistically explained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005102\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 22, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 16, 24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IL17RE\",\n      \"IL17RA\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}