{"gene":"IL17B","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2000,"finding":"IL-17B was cloned and expressed as a novel cytokine (~27% amino acid identity to IL-17A). It stimulates TNF-α and IL-1β release from the monocytic cell line THP-1, binds to THP-1 cells by FACS analysis, but does not bind the human IL-17R extracellular domain and does not induce IL-6 from fibroblasts, indicating it signals through a distinct cognate receptor.","method":"Recombinant protein expression, cytokine induction assay (THP-1 cells), FACS binding assay, IL-17R binding assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (binding assay, functional cytokine induction, receptor exclusion), foundational cloning paper replicated by subsequent studies","pmids":["10639155"],"is_preprint":false},{"year":2007,"finding":"IL-17B induces TNF-α production from mouse peritoneal exudate cells in vitro. In vivo, adoptive transfer of IL-17B-transduced CD4+ T cells exacerbated collagen-induced arthritis, and bone marrow chimeric mice expressing IL-17B showed elevated serum TNF-α and higher arthritis scores. Neutralization of IL-17B suppressed arthritis progression and bone destruction.","method":"In vitro cytokine assay (peritoneal exudate cells), adoptive T cell transfer, bone marrow chimera model, anti-IL-17B neutralizing antibody treatment in CIA mouse model","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vivo and in vitro methods in single lab, clear functional phenotype with neutralization rescue","pmids":["17982105"],"is_preprint":false},{"year":2015,"finding":"IL-17B–IL-17RB signaling in pancreatic cancer activates ERK1/2 pathway to induce CCL20, CXCL1, IL-8, and TFF1 chemokine expression, promoting cancer cell invasion, macrophage and endothelial cell recruitment, and cancer cell survival at distant organs. Anti-IL-17RB monoclonal antibody blocked tumor metastasis and promoted survival in a mouse xenograft model.","method":"Ex vivo cancer cell assays, ERK1/2 pathway inhibition, anti-IL-17RB antibody treatment, mouse xenograft model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (pathway inhibition, antibody blockade, in vivo xenograft), mechanistically defined downstream targets","pmids":["25732306"],"is_preprint":false},{"year":2017,"finding":"IL-17B–IL-17RB signaling promotes resistance to paclitaxel in breast cancer cells via ERK1/2 pathway activation, leading to upregulation of anti-apoptotic BCL-2 family proteins. ERK pathway inhibitor PD98059 completely abolished IL-17B-induced chemoresistance. In vivo, anti-IL-17RB antibody restored tumor chemosensitivity to paclitaxel.","method":"Breast cancer cell line treatment with recombinant IL-17B, ERK1/2 pathway inhibition (PD98059), anti-IL-17RB neutralizing antibody, in vivo mouse tumor model","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Strong — pathway inhibitor rescue, antibody blockade, and in vivo validation, multiple orthogonal methods in single study","pmids":["29371916"],"is_preprint":false},{"year":2017,"finding":"IL-17B activates NF-κB, STAT3, and β-catenin pathways in mesenchymal stem cells and induces expression of stemness-related genes Nanog, Sox2, and Oct4, leading to enhanced tumor-promoting effects including increased gastric cancer cell proliferation and migration.","method":"Recombinant IL-17B treatment of mesenchymal stem cells, pathway activation assays, co-culture/conditioned medium proliferation and migration assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple signaling pathways assessed but mechanistic depth limited; single lab with several readouts","pmids":["28145881"],"is_preprint":false},{"year":2018,"finding":"IL-17B–IL-17RB signaling in lung cancer cells induces ERK phosphorylation, resulting in GSK3β inactivation and β-catenin upregulation. IL-17RB also participates in IL-17B synthesis via the ERK pathway, creating a positive feedback loop that enhances invasion and migration.","method":"IL-17RB overexpression in lung cancer cell lines, ERK/GSK3β/β-catenin pathway analysis, in vitro invasion/migration assays, in vivo metastasis model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — signaling cascade defined with pathway readouts, in vivo validation, single lab","pmids":["29496538"],"is_preprint":false},{"year":2019,"finding":"IL-17B uses both IL-17RA and IL-17RB receptor subunits to elicit type 2 cytokine secretion from innate type 2 lymphocytes, NKT cells, and CD4+ CRTH2+ Th2 cells in the human immune system. IL-17B can also augment IL-33-driven type 2 responses. This receptor requirement (IL-17RA + IL-17RB) mirrors that of IL-25/IL-17E.","method":"Human lymphocyte stimulation assays with recombinant IL-17B, receptor subunit dependency experiments, cytokine secretion assays","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor subunit dependency established with functional readout, single lab","pmids":["30770417"],"is_preprint":false},{"year":2021,"finding":"IL-17B/IL-17RB signaling promotes self-renewal and tumorigenesis of gastric cancer stem cells by inducing K63-linked ubiquitination of Beclin-1, mediated by TRAF6 binding to Beclin-1, thereby activating autophagy. ATG7 knockdown reversed IL-17B-induced self-renewal. IL-17B also induced IL-17RB expression in cancer cells.","method":"Recombinant IL-17B treatment of gastric cancer spheroid cells, Co-IP (TRAF6–Beclin-1 binding), ubiquitination assay, ATG7 knockdown, autophagy markers (LC3, autophagosome formation), IL-17RB silencing, in vivo tumor growth assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — Co-IP for complex, ubiquitination assay, genetic rescue (ATG7 KD), in vivo validation, multiple orthogonal methods","pmids":["33649532"],"is_preprint":false},{"year":2021,"finding":"Tumor-derived IL-17B carried by extracellular vesicles activates pancreatic stellate cells (PSCs) and induces IL-17RB expression in PSCs. Activated PSCs increase oxidative phosphorylation while reducing mitochondrial turnover, then activate tumor cells in a feedback loop that increases tumor cell oxidative phosphorylation and decreases glycolysis partially via IL-6, accelerating tumor growth.","method":"Extracellular vesicle isolation and characterization, IL-17RB overexpression in PSCs, metabolic assays (oxidative phosphorylation, glycolysis), co-injection xenograft mouse model","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo xenograft, metabolic assays, and EV-mediated signaling characterized; single lab","pmids":["34771503"],"is_preprint":false},{"year":2016,"finding":"IL-17B induces IL-8 gene and protein expression in human bronchial epithelial cells (but not lung fibroblasts) via activation of Akt, p38 MAPK, ERK, and NF-κB signaling pathways.","method":"Recombinant IL-17B treatment of bronchial epithelial cells and fibroblasts, signaling pathway inhibition assays, IL-8 gene/protein expression measurement","journal":"Clinical immunology (Orlando, Fla.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling pathways validated with inhibitors, cell-type specificity established; single lab","pmids":["28039016"],"is_preprint":false},{"year":2024,"finding":"Schwann-cell-secreted IL-17B acts in an autocrine manner by binding IL-17RB to promote macrophage recruitment after peripheral nerve injury. Global or Schwann-cell-specific IL-17B deletion reduced macrophage infiltration, myelin clearance, and axon regeneration. IL-17B signaling was found to be defective in injured central nerves.","method":"Mlkl-/- and Sarm1-/- mouse comparison, IL-17B global and Schwann-cell-specific knockout mice, nerve injury model, macrophage infiltration and myelin clearance assays, axon regeneration assessment","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific knockout with defined phenotypic readouts, autocrine signaling mechanism established, multiple genetic models","pmids":["38341853"],"is_preprint":false},{"year":2024,"finding":"IL-17B inhibits B cell activation and differentiation (germinal center B cells and plasma cells) in systemic lupus erythematosus by downregulating FASN-mediated lipid metabolism, thereby inhibiting the Toll-like receptor and interferon pathways. IL-17B deficiency aggravated lupus in lupus-prone mice; recombinant IL-17B alleviated disease.","method":"IL-17B knockout lupus-prone mice, recombinant IL-17B treatment, FASN inhibition/knockdown, B cell activation and differentiation assays, TLR/IFN pathway analysis","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout and recombinant protein rescue, defined molecular mechanism (FASN), single lab","pmids":["39115936"],"is_preprint":false},{"year":2022,"finding":"IL-17B enhances vascular endothelial necroptosis during deep vein thrombosis by upregulating RIP3 and MLKL expression and their phosphorylation. IL-17B promoted IL-6 and TNF-α production downstream of RIP3/MLKL, and this effect was abolished by siRIP3 or siMLKL. Anti-IL-17B antibody reduced necroptosis markers and thrombus formation.","method":"DVT mouse model (IVC ligation), IL-17B knockout mice, anti-IL-17B antibody treatment, siRIP3/siMLKL knockdown in OGD cells, phosphorylation assays for RIP3/MLKL","journal":"Journal of immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and siRNA knockdown with defined phenotype, antibody rescue, single lab","pmids":["36046722"],"is_preprint":false},{"year":2025,"finding":"IL-17B inhibits hepatocellular carcinoma (HCC) cell proliferation and colony formation through an AKT-dependent but NF-κB-independent mechanism, acting via its receptor IL-17RB. This inhibitory effect was not observed in melanoma cells with low IL-17RB expression.","method":"Recombinant IL-17B treatment of HCC cell lines, AKT pathway inhibition, NF-κB inhibition, proliferation and colony formation assays, comparison with IL-17RB-low melanoma cells","journal":"Archivum immunologiae et therapiae experimentalis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic depth in abstract; AKT-dependence stated but mutagenesis/reconstitution not described","pmids":["40544497"],"is_preprint":false},{"year":2025,"finding":"hBD-1 overexpression suppresses the IL-17B/IL-17RB/TRAF6/NF-κB signaling axis in HNSCC by downregulating IL-17B and IL-17RB expression, inhibiting TRAF6 ubiquitination, and decreasing NF-κB pathway phosphorylation, thereby inhibiting tumor cell invasion, migration, and promoting apoptosis.","method":"Stable hBD-1-overexpressing HNSCC cell lines, ubiquitination assay for TRAF6, NF-κB phosphorylation assay, in vivo xenograft model","journal":"Journal of cranio-maxillo-facial surgery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — IL-17B appears as downstream target of hBD-1 suppression; mechanism of IL-17B itself is inferred rather than directly tested; single lab","pmids":["40908208"],"is_preprint":false},{"year":2002,"finding":"IL-17B mRNA and protein are primarily expressed in neuronal cell bodies and axons of human and mouse spinal cord, dorsal root ganglia, and brain, as determined by in situ hybridization and immunohistochemistry. Expression begins at embryonic day 11 in mice and peaks at day 15.","method":"Northern blot, in situ hybridization, immunohistochemistry, radiation hybrid mapping","journal":"Neuromuscular disorders : NMD","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple direct localization methods (ISH + IHC), consistent results; no functional consequence linked to localization","pmids":["11738356"],"is_preprint":false},{"year":2012,"finding":"Recombinant human IL-17B protein binds to its receptor on THP-1 cells with high affinity (FACS), stimulates THP-1 cells to secrete IL-1β and TNF-α in a dose-dependent manner in vitro, and induces neutrophil influx into the peritoneal cavity in vivo upon intraperitoneal injection.","method":"Eukaryotic expression (293T cells), FACS receptor binding, ELISA for cytokine secretion, in vivo peritoneal neutrophil recruitment assay","journal":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — confirmatory study using recombinant protein, single lab, limited novel mechanistic insight beyond original cloning paper","pmids":["22394632"],"is_preprint":false},{"year":2026,"finding":"IL-17B deficiency increases M1-type macrophage infiltration in UPEC-infected kidneys and worsens kidney injury. Recombinant IL-17B treatment reduces macrophage infiltration by modulating chemokine expression (CCL2, CCL3, CCL7), indicating IL-17B regulates macrophage recruitment through chemokine regulation.","method":"IL-17B knockout mice, UPEC infection model, macrophage phenotyping, recombinant IL-17B treatment, chemokine expression analysis","journal":"Microbiology spectrum","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout and recombinant protein rescue with defined molecular mediators (CCL2/3/7), single lab","pmids":["42065596"],"is_preprint":false}],"current_model":"IL-17B is a secreted cytokine that signals primarily through a heterodimeric receptor complex of IL-17RA and IL-17RB to activate ERK1/2, NF-κB, Akt, p38 MAPK, STAT3, and β-catenin pathways, inducing pro-inflammatory mediators (TNF-α, IL-1β, IL-8, CCL20, CXCL1) in monocytes and epithelial cells; in cancer contexts it promotes metastasis, chemoresistance, and cancer stem cell self-renewal via ERK-driven BCL-2 upregulation and TRAF6-mediated K63-ubiquitination of Beclin-1 to activate autophagy; in peripheral nerves, Schwann-cell-secreted IL-17B acts autocrinally via IL-17RB to recruit macrophages for myelin clearance and axon regeneration; and in certain immune and infectious contexts IL-17B can also exert anti-inflammatory effects by suppressing FASN-mediated B cell differentiation and modulating macrophage infiltration through CCL2/3/7 chemokines."},"narrative":{"mechanistic_narrative":"IL-17B is a secreted member of the IL-17 cytokine family that signals through the IL-17RB receptor to drive context-dependent inflammatory, regenerative, and tumor-modulating programs [PMID:10639155, PMID:25732306]. It was originally identified as a cytokine that induces TNF-α and IL-1β from monocytic cells via a receptor distinct from the IL-17A receptor [PMID:10639155], and in human lymphocytes it engages a heterodimeric IL-17RA/IL-17RB complex to elicit type 2 cytokine responses akin to IL-25 [PMID:30770417]. A dominant theme across cancer contexts is IL-17B–IL-17RB activation of ERK1/2 signaling, which induces pro-metastatic chemokines (CCL20, CXCL1, IL-8, TFF1) and macrophage/endothelial recruitment in pancreatic cancer [PMID:25732306], confers paclitaxel resistance through anti-apoptotic BCL-2 family upregulation in breast cancer [PMID:29371916], and inactivates GSK3β to stabilize β-catenin in lung cancer within a positive feedback loop that further drives IL-17B production [PMID:29496538]. IL-17B also promotes cancer stem cell self-renewal by inducing TRAF6-mediated K63-linked ubiquitination of Beclin-1 to activate autophagy [PMID:33649532], and signals through NF-κB, STAT3, and β-catenin to induce stemness genes in mesenchymal stem cells [PMID:28145881]. In epithelial cells, IL-17B induces IL-8 via Akt, p38 MAPK, ERK, and NF-κB pathways [PMID:28039016]. Beyond cancer, Schwann-cell-secreted IL-17B acts autocrinally through IL-17RB to recruit macrophages for myelin clearance and axon regeneration after peripheral nerve injury [PMID:38341853], and in several immune settings IL-17B exerts protective or anti-inflammatory roles, suppressing FASN-dependent B cell differentiation in lupus [PMID:39115936] and modulating macrophage infiltration through CCL2/CCL3/CCL7 in infected kidney [PMID:42065596]. IL-17B is prominently expressed in neuronal cell bodies and axons of the spinal cord, dorsal root ganglia, and brain [PMID:11738356].","teleology":[{"year":2000,"claim":"Establishing IL-17B as a distinct cytokine that signals through its own receptor answered whether it functions independently of IL-17A and where it acts.","evidence":"Recombinant protein expression with THP-1 cytokine induction, FACS binding, and IL-17R exclusion assays","pmids":["10639155"],"confidence":"High","gaps":["Cognate receptor not identified in this study","Signaling pathway downstream of binding undefined"]},{"year":2002,"claim":"Mapping IL-17B expression to neurons addressed where the cytokine is produced, hinting at a nervous-system role distinct from classical immune cytokines.","evidence":"Northern blot, in situ hybridization, and immunohistochemistry in human and mouse CNS/DRG","pmids":["11738356"],"confidence":"Medium","gaps":["No functional consequence linked to neuronal localization","Receptor-bearing target cells not identified"]},{"year":2007,"claim":"Demonstrating that IL-17B drives TNF-α and exacerbates arthritis established it as a pro-inflammatory effector with disease relevance in vivo.","evidence":"In vitro peritoneal cytokine assay, adoptive T cell transfer, bone marrow chimera, and neutralizing antibody in collagen-induced arthritis","pmids":["17982105"],"confidence":"Medium","gaps":["Receptor and signaling pathway not defined","Cellular source in arthritis unresolved"]},{"year":2015,"claim":"Defining the IL-17B–IL-17RB–ERK1/2 axis and its chemokine outputs explained how IL-17B promotes tumor invasion and metastatic niche formation.","evidence":"Cancer cell assays, ERK1/2 inhibition, anti-IL-17RB antibody, and mouse xenograft in pancreatic cancer","pmids":["25732306"],"confidence":"High","gaps":["Receptor co-subunit requirement not addressed","Upstream receptor-proximal adaptors unresolved"]},{"year":2016,"claim":"Identifying the Akt/p38/ERK/NF-κB pathways for IL-8 induction in bronchial epithelium clarified cell-type-specific epithelial responses to IL-17B.","evidence":"Recombinant IL-17B treatment with pathway inhibitors in bronchial epithelial cells versus fibroblasts","pmids":["28039016"],"confidence":"Medium","gaps":["Basis of fibroblast non-responsiveness not defined","Receptor subunit usage in epithelium unaddressed"]},{"year":2017,"claim":"Linking ERK-driven BCL-2 upregulation to chemoresistance, and NF-κB/STAT3/β-catenin to stemness, expanded IL-17B's tumor-promoting repertoire beyond invasion.","evidence":"Recombinant IL-17B with ERK inhibitor rescue and anti-IL-17RB antibody in breast cancer; pathway and stemness gene assays in mesenchymal stem cells","pmids":["29371916","28145881"],"confidence":"High","gaps":["Connection between distinct pathway outputs not unified mechanistically","MSC findings of lower mechanistic depth"]},{"year":2018,"claim":"Showing ERK-mediated GSK3β inactivation and a positive feedback loop on IL-17B synthesis established a self-amplifying circuit driving cancer cell migration.","evidence":"IL-17RB overexpression, ERK/GSK3β/β-catenin pathway analysis, invasion/migration and in vivo metastasis assays in lung cancer","pmids":["29496538"],"confidence":"Medium","gaps":["Mechanism of ERK-driven IL-17B transcription not defined","Feedback loop not validated in primary tumors"]},{"year":2019,"claim":"Establishing that IL-17B requires both IL-17RA and IL-17RB for type 2 cytokine induction defined its functional receptor complex, mirroring IL-25.","evidence":"Human lymphocyte stimulation with receptor subunit dependency and cytokine secretion assays","pmids":["30770417"],"confidence":"Medium","gaps":["Stoichiometry and structure of the receptor complex unresolved","Whether all IL-17B activities require IL-17RA unknown"]},{"year":2021,"claim":"Identifying TRAF6-mediated K63-ubiquitination of Beclin-1 and autophagy activation provided a molecular mechanism for IL-17B-driven cancer stem cell self-renewal.","evidence":"Recombinant IL-17B on gastric cancer spheroids, TRAF6–Beclin-1 Co-IP, ubiquitination assay, ATG7 knockdown rescue, in vivo growth; EV-mediated stellate cell activation and metabolic reprogramming in pancreatic cancer","pmids":["33649532","34771503"],"confidence":"High","gaps":["How IL-17RB signaling recruits TRAF6 to Beclin-1 not defined","EV-mediated delivery characterized in single lab"]},{"year":2022,"claim":"Demonstrating IL-17B promotion of RIP3/MLKL-dependent endothelial necroptosis extended its pro-inflammatory role to vascular thrombosis.","evidence":"DVT mouse model, IL-17B knockout, anti-IL-17B antibody, and siRIP3/siMLKL knockdown with phosphorylation assays","pmids":["36046722"],"confidence":"Medium","gaps":["Receptor mediating necroptotic signaling not identified","Link between IL-17B and RIP3 upregulation undefined"]},{"year":2024,"claim":"Cell-type-specific knockouts revealed an autocrine Schwann-cell IL-17B program for macrophage recruitment and nerve regeneration, and a FASN-suppressing protective role in autoimmunity.","evidence":"Schwann-cell-specific and global IL-17B knockout in nerve injury with macrophage/myelin/axon readouts; IL-17B knockout and recombinant rescue with FASN inhibition in lupus-prone mice","pmids":["38341853","39115936"],"confidence":"High","gaps":["Why central nerve IL-17B signaling is defective unresolved","How IL-17B regulates FASN mechanistically not fully defined"]},{"year":2025,"claim":"Reports of AKT-dependent growth inhibition in hepatocellular carcinoma and suppression of IL-17B/IL-17RB/TRAF6/NF-κB by hBD-1 in HNSCC point to context-dependent and tumor-suppressive facets of IL-17B signaling.","evidence":"Recombinant IL-17B with AKT/NF-κB inhibition in HCC cells; hBD-1 overexpression with TRAF6 ubiquitination and NF-κB assays in HNSCC","pmids":["40544497","40908208"],"confidence":"Low","gaps":["AKT-dependence stated without mutagenesis or reconstitution","IL-17B mechanism in HNSCC inferred as downstream target rather than directly tested"]},{"year":2026,"claim":"Showing that IL-17B restrains M1 macrophage infiltration via CCL2/CCL3/CCL7 reinforced its capacity for anti-inflammatory, tissue-protective chemokine modulation in infection.","evidence":"IL-17B knockout mice in UPEC kidney infection, macrophage phenotyping, recombinant IL-17B rescue, and chemokine expression analysis","pmids":["42065596"],"confidence":"Medium","gaps":["Receptor and signaling pathway for chemokine modulation undefined","Direct versus indirect chemokine regulation unresolved"]},{"year":null,"claim":"It remains unresolved how a single cytokine produces opposing pro-inflammatory/pro-tumorigenic and anti-inflammatory/tumor-suppressive outcomes, and what receptor-proximal and cell-context determinants switch between these programs.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the IL-17B–receptor complex","Determinants of ERK-pro-tumor versus AKT-suppressive outcomes unknown","Whether IL-17RA is required across all activities unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,2,6,16]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,10,15]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,6,11,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,5,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]}],"complexes":[],"partners":["IL17RB","IL17RA","TRAF6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UHF5","full_name":"Interleukin-17B","aliases":["Cytokine Zcyto7","Interleukin-20","IL-20","Neuronal interleukin-17-related factor"],"length_aa":180,"mass_kda":20.4,"function":"Stimulates the release of tumor necrosis factor alpha and IL-1-beta from the monocytic cell line THP-1","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9UHF5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL17B","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL17B","total_profiled":1310},"omim":[{"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"},{"mim_id":"604627","title":"INTERLEUKIN 17B; IL17B","url":"https://www.omim.org/entry/604627"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":10.6}],"url":"https://www.proteinatlas.org/search/IL17B"},"hgnc":{"alias_symbol":["IL-17B","ZCYTO7","IL-20","MGC138900","MGC138901","NIRF"],"prev_symbol":[]},"alphafold":{"accession":"Q9UHF5","domains":[{"cath_id":"2.10.90.10","chopping":"57-178","consensus_level":"high","plddt":91.2105,"start":57,"end":178}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHF5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHF5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHF5-F1-predicted_aligned_error_v6.png","plddt_mean":78.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL17B","jax_strain_url":"https://www.jax.org/strain/search?query=IL17B"},"sequence":{"accession":"Q9UHF5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UHF5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UHF5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHF5"}},"corpus_meta":[{"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":"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":"25732306","id":"PMC_25732306","title":"Targeting IL-17B-IL-17RB signaling with an anti-IL-17RB antibody blocks pancreatic cancer metastasis by silencing multiple chemokines.","date":"2015","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25732306","citation_count":139,"is_preprint":false},{"pmid":"28704706","id":"PMC_28704706","title":"IL-17B: A new area of study in the IL-17 family.","date":"2017","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28704706","citation_count":70,"is_preprint":false},{"pmid":"32373132","id":"PMC_32373132","title":"The Emerging Role of the IL-17B/IL-17RB Pathway in Cancer.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32373132","citation_count":64,"is_preprint":false},{"pmid":"28160754","id":"PMC_28160754","title":"The role of IL17B-IL17RB signaling pathway in breast cancer.","date":"2017","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/28160754","citation_count":59,"is_preprint":false},{"pmid":"17827167","id":"PMC_17827167","title":"Immunolocalization of IL-17A, IL-17B, and their receptors in chondrocytes during 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peripheral nerves.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38341853","citation_count":36,"is_preprint":false},{"pmid":"29496538","id":"PMC_29496538","title":"A positive feedback loop of IL-17B-IL-17RB activates ERK/β-catenin to promote lung cancer metastasis.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/29496538","citation_count":36,"is_preprint":false},{"pmid":"28145881","id":"PMC_28145881","title":"IL-17B activated mesenchymal stem cells enhance proliferation and migration of gastric cancer cells.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28145881","citation_count":35,"is_preprint":false},{"pmid":"33649532","id":"PMC_33649532","title":"IL-17B/IL-17RB signaling cascade contributes to self-renewal and tumorigenesis of cancer stem cells by regulating Beclin-1 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Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/28039016","citation_count":15,"is_preprint":false},{"pmid":"20467469","id":"PMC_20467469","title":"IL-17B Can Impact on Endothelial Cellular Traits Linked to Tumour Angiogenesis.","date":"2010","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/20467469","citation_count":15,"is_preprint":false},{"pmid":"34771503","id":"PMC_34771503","title":"IL-17B/RB Activation in Pancreatic Stellate Cells Promotes Pancreatic Cancer Metabolism and Growth.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34771503","citation_count":13,"is_preprint":false},{"pmid":"31675522","id":"PMC_31675522","title":"Effects of porcine IL-17B and IL-17E against intestinal pathogenic microorganism.","date":"2019","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31675522","citation_count":6,"is_preprint":false},{"pmid":"39115936","id":"PMC_39115936","title":"IL-17B alleviates the pathogenesis of systemic lupus erythematosus by inhibiting FASN-mediated differentiation of B cells.","date":"2024","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/39115936","citation_count":5,"is_preprint":false},{"pmid":"36046722","id":"PMC_36046722","title":"Necroptosis Plays a Crucial Role in Vascular Injury during DVT and Is Enhanced by IL-17B.","date":"2022","source":"Journal of immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/36046722","citation_count":4,"is_preprint":false},{"pmid":"29511476","id":"PMC_29511476","title":"Evaluation of IL-17B and IL-17F mRNA expression in peripheral blood mononuclear cells and association with clinical outcome of IBD patients.","date":"2017","source":"Gastroenterology and hepatology from bed to bench","url":"https://pubmed.ncbi.nlm.nih.gov/29511476","citation_count":3,"is_preprint":false},{"pmid":"40544497","id":"PMC_40544497","title":"IL-17B Inhibits Hepatocellular Carcinoma Cell Proliferation.","date":"2025","source":"Archivum immunologiae et therapiae experimentalis","url":"https://pubmed.ncbi.nlm.nih.gov/40544497","citation_count":1,"is_preprint":false},{"pmid":"40908208","id":"PMC_40908208","title":"The molecular mechanism of human beta-defensin 1 in inhibiting the progression of head and neck squamous cell carcinoma: The role of the IL-17B/IL-17RB/TRAF6/NF-κB signaling axis.","date":"2025","source":"Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery","url":"https://pubmed.ncbi.nlm.nih.gov/40908208","citation_count":1,"is_preprint":false},{"pmid":"38033168","id":"PMC_38033168","title":"Variants of IL6, IL10, FCN2, RNASE3, IL12B and IL17B loci are associated with Schistosoma mansoni worm burden in the Albert Nile region of Uganda.","date":"2023","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/38033168","citation_count":1,"is_preprint":false},{"pmid":"42065596","id":"PMC_42065596","title":"IL-17B protects against uropathogenic E. coli-induced kidney injury via macrophage infiltration modulation.","date":"2026","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/42065596","citation_count":0,"is_preprint":false},{"pmid":"22394632","id":"PMC_22394632","title":"[Eukaryotic expression and biological activity of recombinant human IL-17B protein].","date":"2012","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/22394632","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14642,"output_tokens":4771,"usd":0.057745,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13048,"output_tokens":4474,"usd":0.088545,"stage2_stop_reason":"end_turn"},"total_usd":0.14629,"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-17B was cloned and expressed as a novel cytokine (~27% amino acid identity to IL-17A). It stimulates TNF-α and IL-1β release from the monocytic cell line THP-1, binds to THP-1 cells by FACS analysis, but does not bind the human IL-17R extracellular domain and does not induce IL-6 from fibroblasts, indicating it signals through a distinct cognate receptor.\",\n      \"method\": \"Recombinant protein expression, cytokine induction assay (THP-1 cells), FACS binding assay, IL-17R binding assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (binding assay, functional cytokine induction, receptor exclusion), foundational cloning paper replicated by subsequent studies\",\n      \"pmids\": [\"10639155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IL-17B induces TNF-α production from mouse peritoneal exudate cells in vitro. In vivo, adoptive transfer of IL-17B-transduced CD4+ T cells exacerbated collagen-induced arthritis, and bone marrow chimeric mice expressing IL-17B showed elevated serum TNF-α and higher arthritis scores. Neutralization of IL-17B suppressed arthritis progression and bone destruction.\",\n      \"method\": \"In vitro cytokine assay (peritoneal exudate cells), adoptive T cell transfer, bone marrow chimera model, anti-IL-17B neutralizing antibody treatment in CIA mouse model\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vivo and in vitro methods in single lab, clear functional phenotype with neutralization rescue\",\n      \"pmids\": [\"17982105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-17B–IL-17RB signaling in pancreatic cancer activates ERK1/2 pathway to induce CCL20, CXCL1, IL-8, and TFF1 chemokine expression, promoting cancer cell invasion, macrophage and endothelial cell recruitment, and cancer cell survival at distant organs. Anti-IL-17RB monoclonal antibody blocked tumor metastasis and promoted survival in a mouse xenograft model.\",\n      \"method\": \"Ex vivo cancer cell assays, ERK1/2 pathway inhibition, anti-IL-17RB antibody treatment, mouse xenograft model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (pathway inhibition, antibody blockade, in vivo xenograft), mechanistically defined downstream targets\",\n      \"pmids\": [\"25732306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-17B–IL-17RB signaling promotes resistance to paclitaxel in breast cancer cells via ERK1/2 pathway activation, leading to upregulation of anti-apoptotic BCL-2 family proteins. ERK pathway inhibitor PD98059 completely abolished IL-17B-induced chemoresistance. In vivo, anti-IL-17RB antibody restored tumor chemosensitivity to paclitaxel.\",\n      \"method\": \"Breast cancer cell line treatment with recombinant IL-17B, ERK1/2 pathway inhibition (PD98059), anti-IL-17RB neutralizing antibody, in vivo mouse tumor model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pathway inhibitor rescue, antibody blockade, and in vivo validation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"29371916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-17B activates NF-κB, STAT3, and β-catenin pathways in mesenchymal stem cells and induces expression of stemness-related genes Nanog, Sox2, and Oct4, leading to enhanced tumor-promoting effects including increased gastric cancer cell proliferation and migration.\",\n      \"method\": \"Recombinant IL-17B treatment of mesenchymal stem cells, pathway activation assays, co-culture/conditioned medium proliferation and migration assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple signaling pathways assessed but mechanistic depth limited; single lab with several readouts\",\n      \"pmids\": [\"28145881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-17B–IL-17RB signaling in lung cancer cells induces ERK phosphorylation, resulting in GSK3β inactivation and β-catenin upregulation. IL-17RB also participates in IL-17B synthesis via the ERK pathway, creating a positive feedback loop that enhances invasion and migration.\",\n      \"method\": \"IL-17RB overexpression in lung cancer cell lines, ERK/GSK3β/β-catenin pathway analysis, in vitro invasion/migration assays, in vivo metastasis model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — signaling cascade defined with pathway readouts, in vivo validation, single lab\",\n      \"pmids\": [\"29496538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17B uses both IL-17RA and IL-17RB receptor subunits to elicit type 2 cytokine secretion from innate type 2 lymphocytes, NKT cells, and CD4+ CRTH2+ Th2 cells in the human immune system. IL-17B can also augment IL-33-driven type 2 responses. This receptor requirement (IL-17RA + IL-17RB) mirrors that of IL-25/IL-17E.\",\n      \"method\": \"Human lymphocyte stimulation assays with recombinant IL-17B, receptor subunit dependency experiments, cytokine secretion assays\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor subunit dependency established with functional readout, single lab\",\n      \"pmids\": [\"30770417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-17B/IL-17RB signaling promotes self-renewal and tumorigenesis of gastric cancer stem cells by inducing K63-linked ubiquitination of Beclin-1, mediated by TRAF6 binding to Beclin-1, thereby activating autophagy. ATG7 knockdown reversed IL-17B-induced self-renewal. IL-17B also induced IL-17RB expression in cancer cells.\",\n      \"method\": \"Recombinant IL-17B treatment of gastric cancer spheroid cells, Co-IP (TRAF6–Beclin-1 binding), ubiquitination assay, ATG7 knockdown, autophagy markers (LC3, autophagosome formation), IL-17RB silencing, in vivo tumor growth assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — Co-IP for complex, ubiquitination assay, genetic rescue (ATG7 KD), in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"33649532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tumor-derived IL-17B carried by extracellular vesicles activates pancreatic stellate cells (PSCs) and induces IL-17RB expression in PSCs. Activated PSCs increase oxidative phosphorylation while reducing mitochondrial turnover, then activate tumor cells in a feedback loop that increases tumor cell oxidative phosphorylation and decreases glycolysis partially via IL-6, accelerating tumor growth.\",\n      \"method\": \"Extracellular vesicle isolation and characterization, IL-17RB overexpression in PSCs, metabolic assays (oxidative phosphorylation, glycolysis), co-injection xenograft mouse model\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo xenograft, metabolic assays, and EV-mediated signaling characterized; single lab\",\n      \"pmids\": [\"34771503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-17B induces IL-8 gene and protein expression in human bronchial epithelial cells (but not lung fibroblasts) via activation of Akt, p38 MAPK, ERK, and NF-κB signaling pathways.\",\n      \"method\": \"Recombinant IL-17B treatment of bronchial epithelial cells and fibroblasts, signaling pathway inhibition assays, IL-8 gene/protein expression measurement\",\n      \"journal\": \"Clinical immunology (Orlando, Fla.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling pathways validated with inhibitors, cell-type specificity established; single lab\",\n      \"pmids\": [\"28039016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Schwann-cell-secreted IL-17B acts in an autocrine manner by binding IL-17RB to promote macrophage recruitment after peripheral nerve injury. Global or Schwann-cell-specific IL-17B deletion reduced macrophage infiltration, myelin clearance, and axon regeneration. IL-17B signaling was found to be defective in injured central nerves.\",\n      \"method\": \"Mlkl-/- and Sarm1-/- mouse comparison, IL-17B global and Schwann-cell-specific knockout mice, nerve injury model, macrophage infiltration and myelin clearance assays, axon regeneration assessment\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific knockout with defined phenotypic readouts, autocrine signaling mechanism established, multiple genetic models\",\n      \"pmids\": [\"38341853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-17B inhibits B cell activation and differentiation (germinal center B cells and plasma cells) in systemic lupus erythematosus by downregulating FASN-mediated lipid metabolism, thereby inhibiting the Toll-like receptor and interferon pathways. IL-17B deficiency aggravated lupus in lupus-prone mice; recombinant IL-17B alleviated disease.\",\n      \"method\": \"IL-17B knockout lupus-prone mice, recombinant IL-17B treatment, FASN inhibition/knockdown, B cell activation and differentiation assays, TLR/IFN pathway analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout and recombinant protein rescue, defined molecular mechanism (FASN), single lab\",\n      \"pmids\": [\"39115936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-17B enhances vascular endothelial necroptosis during deep vein thrombosis by upregulating RIP3 and MLKL expression and their phosphorylation. IL-17B promoted IL-6 and TNF-α production downstream of RIP3/MLKL, and this effect was abolished by siRIP3 or siMLKL. Anti-IL-17B antibody reduced necroptosis markers and thrombus formation.\",\n      \"method\": \"DVT mouse model (IVC ligation), IL-17B knockout mice, anti-IL-17B antibody treatment, siRIP3/siMLKL knockdown in OGD cells, phosphorylation assays for RIP3/MLKL\",\n      \"journal\": \"Journal of immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and siRNA knockdown with defined phenotype, antibody rescue, single lab\",\n      \"pmids\": [\"36046722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-17B inhibits hepatocellular carcinoma (HCC) cell proliferation and colony formation through an AKT-dependent but NF-κB-independent mechanism, acting via its receptor IL-17RB. This inhibitory effect was not observed in melanoma cells with low IL-17RB expression.\",\n      \"method\": \"Recombinant IL-17B treatment of HCC cell lines, AKT pathway inhibition, NF-κB inhibition, proliferation and colony formation assays, comparison with IL-17RB-low melanoma cells\",\n      \"journal\": \"Archivum immunologiae et therapiae experimentalis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic depth in abstract; AKT-dependence stated but mutagenesis/reconstitution not described\",\n      \"pmids\": [\"40544497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"hBD-1 overexpression suppresses the IL-17B/IL-17RB/TRAF6/NF-κB signaling axis in HNSCC by downregulating IL-17B and IL-17RB expression, inhibiting TRAF6 ubiquitination, and decreasing NF-κB pathway phosphorylation, thereby inhibiting tumor cell invasion, migration, and promoting apoptosis.\",\n      \"method\": \"Stable hBD-1-overexpressing HNSCC cell lines, ubiquitination assay for TRAF6, NF-κB phosphorylation assay, in vivo xenograft model\",\n      \"journal\": \"Journal of cranio-maxillo-facial surgery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — IL-17B appears as downstream target of hBD-1 suppression; mechanism of IL-17B itself is inferred rather than directly tested; single lab\",\n      \"pmids\": [\"40908208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IL-17B mRNA and protein are primarily expressed in neuronal cell bodies and axons of human and mouse spinal cord, dorsal root ganglia, and brain, as determined by in situ hybridization and immunohistochemistry. Expression begins at embryonic day 11 in mice and peaks at day 15.\",\n      \"method\": \"Northern blot, in situ hybridization, immunohistochemistry, radiation hybrid mapping\",\n      \"journal\": \"Neuromuscular disorders : NMD\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple direct localization methods (ISH + IHC), consistent results; no functional consequence linked to localization\",\n      \"pmids\": [\"11738356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Recombinant human IL-17B protein binds to its receptor on THP-1 cells with high affinity (FACS), stimulates THP-1 cells to secrete IL-1β and TNF-α in a dose-dependent manner in vitro, and induces neutrophil influx into the peritoneal cavity in vivo upon intraperitoneal injection.\",\n      \"method\": \"Eukaryotic expression (293T cells), FACS receptor binding, ELISA for cytokine secretion, in vivo peritoneal neutrophil recruitment assay\",\n      \"journal\": \"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — confirmatory study using recombinant protein, single lab, limited novel mechanistic insight beyond original cloning paper\",\n      \"pmids\": [\"22394632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"IL-17B deficiency increases M1-type macrophage infiltration in UPEC-infected kidneys and worsens kidney injury. Recombinant IL-17B treatment reduces macrophage infiltration by modulating chemokine expression (CCL2, CCL3, CCL7), indicating IL-17B regulates macrophage recruitment through chemokine regulation.\",\n      \"method\": \"IL-17B knockout mice, UPEC infection model, macrophage phenotyping, recombinant IL-17B treatment, chemokine expression analysis\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout and recombinant protein rescue with defined molecular mediators (CCL2/3/7), single lab\",\n      \"pmids\": [\"42065596\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-17B is a secreted cytokine that signals primarily through a heterodimeric receptor complex of IL-17RA and IL-17RB to activate ERK1/2, NF-κB, Akt, p38 MAPK, STAT3, and β-catenin pathways, inducing pro-inflammatory mediators (TNF-α, IL-1β, IL-8, CCL20, CXCL1) in monocytes and epithelial cells; in cancer contexts it promotes metastasis, chemoresistance, and cancer stem cell self-renewal via ERK-driven BCL-2 upregulation and TRAF6-mediated K63-ubiquitination of Beclin-1 to activate autophagy; in peripheral nerves, Schwann-cell-secreted IL-17B acts autocrinally via IL-17RB to recruit macrophages for myelin clearance and axon regeneration; and in certain immune and infectious contexts IL-17B can also exert anti-inflammatory effects by suppressing FASN-mediated B cell differentiation and modulating macrophage infiltration through CCL2/3/7 chemokines.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL-17B is a secreted member of the IL-17 cytokine family that signals through the IL-17RB receptor to drive context-dependent inflammatory, regenerative, and tumor-modulating programs [#0, #2]. It was originally identified as a cytokine that induces TNF-\\u03b1 and IL-1\\u03b2 from monocytic cells via a receptor distinct from the IL-17A receptor [#0], and in human lymphocytes it engages a heterodimeric IL-17RA/IL-17RB complex to elicit type 2 cytokine responses akin to IL-25 [#6]. A dominant theme across cancer contexts is IL-17B\\u2013IL-17RB activation of ERK1/2 signaling, which induces pro-metastatic chemokines (CCL20, CXCL1, IL-8, TFF1) and macrophage/endothelial recruitment in pancreatic cancer [#2], confers paclitaxel resistance through anti-apoptotic BCL-2 family upregulation in breast cancer [#3], and inactivates GSK3\\u03b2 to stabilize \\u03b2-catenin in lung cancer within a positive feedback loop that further drives IL-17B production [#5]. IL-17B also promotes cancer stem cell self-renewal by inducing TRAF6-mediated K63-linked ubiquitination of Beclin-1 to activate autophagy [#7], and signals through NF-\\u03baB, STAT3, and \\u03b2-catenin to induce stemness genes in mesenchymal stem cells [#4]. In epithelial cells, IL-17B induces IL-8 via Akt, p38 MAPK, ERK, and NF-\\u03baB pathways [#9]. Beyond cancer, Schwann-cell-secreted IL-17B acts autocrinally through IL-17RB to recruit macrophages for myelin clearance and axon regeneration after peripheral nerve injury [#10], and in several immune settings IL-17B exerts protective or anti-inflammatory roles, suppressing FASN-dependent B cell differentiation in lupus [#11] and modulating macrophage infiltration through CCL2/CCL3/CCL7 in infected kidney [#17]. IL-17B is prominently expressed in neuronal cell bodies and axons of the spinal cord, dorsal root ganglia, and brain [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing IL-17B as a distinct cytokine that signals through its own receptor answered whether it functions independently of IL-17A and where it acts.\",\n      \"evidence\": \"Recombinant protein expression with THP-1 cytokine induction, FACS binding, and IL-17R exclusion assays\",\n      \"pmids\": [\"10639155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cognate receptor not identified in this study\", \"Signaling pathway downstream of binding undefined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapping IL-17B expression to neurons addressed where the cytokine is produced, hinting at a nervous-system role distinct from classical immune cytokines.\",\n      \"evidence\": \"Northern blot, in situ hybridization, and immunohistochemistry in human and mouse CNS/DRG\",\n      \"pmids\": [\"11738356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence linked to neuronal localization\", \"Receptor-bearing target cells not identified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that IL-17B drives TNF-\\u03b1 and exacerbates arthritis established it as a pro-inflammatory effector with disease relevance in vivo.\",\n      \"evidence\": \"In vitro peritoneal cytokine assay, adoptive T cell transfer, bone marrow chimera, and neutralizing antibody in collagen-induced arthritis\",\n      \"pmids\": [\"17982105\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor and signaling pathway not defined\", \"Cellular source in arthritis unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defining the IL-17B\\u2013IL-17RB\\u2013ERK1/2 axis and its chemokine outputs explained how IL-17B promotes tumor invasion and metastatic niche formation.\",\n      \"evidence\": \"Cancer cell assays, ERK1/2 inhibition, anti-IL-17RB antibody, and mouse xenograft in pancreatic cancer\",\n      \"pmids\": [\"25732306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor co-subunit requirement not addressed\", \"Upstream receptor-proximal adaptors unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying the Akt/p38/ERK/NF-\\u03baB pathways for IL-8 induction in bronchial epithelium clarified cell-type-specific epithelial responses to IL-17B.\",\n      \"evidence\": \"Recombinant IL-17B treatment with pathway inhibitors in bronchial epithelial cells versus fibroblasts\",\n      \"pmids\": [\"28039016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis of fibroblast non-responsiveness not defined\", \"Receptor subunit usage in epithelium unaddressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linking ERK-driven BCL-2 upregulation to chemoresistance, and NF-\\u03baB/STAT3/\\u03b2-catenin to stemness, expanded IL-17B's tumor-promoting repertoire beyond invasion.\",\n      \"evidence\": \"Recombinant IL-17B with ERK inhibitor rescue and anti-IL-17RB antibody in breast cancer; pathway and stemness gene assays in mesenchymal stem cells\",\n      \"pmids\": [\"29371916\", \"28145881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Connection between distinct pathway outputs not unified mechanistically\", \"MSC findings of lower mechanistic depth\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing ERK-mediated GSK3\\u03b2 inactivation and a positive feedback loop on IL-17B synthesis established a self-amplifying circuit driving cancer cell migration.\",\n      \"evidence\": \"IL-17RB overexpression, ERK/GSK3\\u03b2/\\u03b2-catenin pathway analysis, invasion/migration and in vivo metastasis assays in lung cancer\",\n      \"pmids\": [\"29496538\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ERK-driven IL-17B transcription not defined\", \"Feedback loop not validated in primary tumors\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing that IL-17B requires both IL-17RA and IL-17RB for type 2 cytokine induction defined its functional receptor complex, mirroring IL-25.\",\n      \"evidence\": \"Human lymphocyte stimulation with receptor subunit dependency and cytokine secretion assays\",\n      \"pmids\": [\"30770417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and structure of the receptor complex unresolved\", \"Whether all IL-17B activities require IL-17RA unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying TRAF6-mediated K63-ubiquitination of Beclin-1 and autophagy activation provided a molecular mechanism for IL-17B-driven cancer stem cell self-renewal.\",\n      \"evidence\": \"Recombinant IL-17B on gastric cancer spheroids, TRAF6\\u2013Beclin-1 Co-IP, ubiquitination assay, ATG7 knockdown rescue, in vivo growth; EV-mediated stellate cell activation and metabolic reprogramming in pancreatic cancer\",\n      \"pmids\": [\"33649532\", \"34771503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IL-17RB signaling recruits TRAF6 to Beclin-1 not defined\", \"EV-mediated delivery characterized in single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating IL-17B promotion of RIP3/MLKL-dependent endothelial necroptosis extended its pro-inflammatory role to vascular thrombosis.\",\n      \"evidence\": \"DVT mouse model, IL-17B knockout, anti-IL-17B antibody, and siRIP3/siMLKL knockdown with phosphorylation assays\",\n      \"pmids\": [\"36046722\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating necroptotic signaling not identified\", \"Link between IL-17B and RIP3 upregulation undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cell-type-specific knockouts revealed an autocrine Schwann-cell IL-17B program for macrophage recruitment and nerve regeneration, and a FASN-suppressing protective role in autoimmunity.\",\n      \"evidence\": \"Schwann-cell-specific and global IL-17B knockout in nerve injury with macrophage/myelin/axon readouts; IL-17B knockout and recombinant rescue with FASN inhibition in lupus-prone mice\",\n      \"pmids\": [\"38341853\", \"39115936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why central nerve IL-17B signaling is defective unresolved\", \"How IL-17B regulates FASN mechanistically not fully defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reports of AKT-dependent growth inhibition in hepatocellular carcinoma and suppression of IL-17B/IL-17RB/TRAF6/NF-\\u03baB by hBD-1 in HNSCC point to context-dependent and tumor-suppressive facets of IL-17B signaling.\",\n      \"evidence\": \"Recombinant IL-17B with AKT/NF-\\u03baB inhibition in HCC cells; hBD-1 overexpression with TRAF6 ubiquitination and NF-\\u03baB assays in HNSCC\",\n      \"pmids\": [\"40544497\", \"40908208\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"AKT-dependence stated without mutagenesis or reconstitution\", \"IL-17B mechanism in HNSCC inferred as downstream target rather than directly tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showing that IL-17B restrains M1 macrophage infiltration via CCL2/CCL3/CCL7 reinforced its capacity for anti-inflammatory, tissue-protective chemokine modulation in infection.\",\n      \"evidence\": \"IL-17B knockout mice in UPEC kidney infection, macrophage phenotyping, recombinant IL-17B rescue, and chemokine expression analysis\",\n      \"pmids\": [\"42065596\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor and signaling pathway for chemokine modulation undefined\", \"Direct versus indirect chemokine regulation unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single cytokine produces opposing pro-inflammatory/pro-tumorigenic and anti-inflammatory/tumor-suppressive outcomes, and what receptor-proximal and cell-context determinants switch between these programs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the IL-17B\\u2013receptor complex\", \"Determinants of ERK-pro-tumor versus AKT-suppressive outcomes unknown\", \"Whether IL-17RA is required across all activities unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 2, 6, 16]},\n      {\"term_id\": \"GO:0005102\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 10, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 6, 11, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 5, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IL17RB\", \"IL17RA\", \"TRAF6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}