{"gene":"IL17B","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2000,"finding":"IL-17B was cloned and found to stimulate TNF-alpha and IL-1beta release from the monocytic cell line THP-1, while failing to bind the IL-17 receptor extracellular domain or induce IL-6 from fibroblasts, establishing it as a distinct IL-17 family member with a separate receptor.","method":"Recombinant protein expression, FACS binding assay, cytokine induction assay in THP-1 cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — original cloning paper with in vitro functional assays and receptor binding characterization","pmids":["10639155"],"is_preprint":false},{"year":2002,"finding":"IL-17B mRNA and protein are primarily expressed by neurons in spinal cord, dorsal root ganglia, and brain (neuronal cell bodies and axons), as determined by Northern analysis, in situ hybridization, and immunohistochemistry.","method":"Northern blot, in situ hybridization, immunohistochemistry","journal":"Neuromuscular disorders : NMD","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal localization methods in human and mouse tissues","pmids":["11738356"],"is_preprint":false},{"year":2007,"finding":"IL-17B and IL-17C stimulate TNF-alpha production from mouse peritoneal exudate cells in vitro, and adoptive transfer of IL-17B-transduced CD4+ T cells exacerbates collagen-induced arthritis in vivo; neutralization of IL-17B significantly suppressed arthritis progression and bone destruction.","method":"In vitro cytokine induction assay, adoptive T cell transfer, bone marrow chimeric mice, anti-IL-17B neutralizing antibody treatment in CIA model","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 — multiple in vivo and in vitro methods with loss-of-function neutralization and defined phenotypic readouts","pmids":["17982105"],"is_preprint":false},{"year":2007,"finding":"IL-17B and IL-17C are expressed in cartilage and chondrocytes during fracture healing and in the epiphyseal growth plate, with localization paralleling that of IL-17R and IL-17RL, suggesting a role in endochondral differentiation.","method":"Immunolocalization (immunohistochemistry) in fracture callus and growth plate","journal":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","confidence":"Low","confidence_rationale":"Tier 3 — single localization method without functional mechanistic follow-up","pmids":["17827167"],"is_preprint":false},{"year":2015,"finding":"IL-17B–IL-17RB signaling activates the ERK1/2 pathway to upregulate CCL20, CXCL1, IL-8, and TFF1 chemokines, promoting pancreatic cancer cell invasion, macrophage and endothelial cell recruitment, and cancer cell survival at distant sites; anti-IL-17RB antibody blocked tumor metastasis in a xenograft model.","method":"Ex vivo experiments with IL-17B/IL-17RB overexpression, ERK1/2 pathway analysis, xenograft mouse model, monoclonal antibody blockade","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including pathway analysis, in vivo xenograft, and antibody blockade with defined molecular mechanism","pmids":["25732306"],"is_preprint":false},{"year":2017,"finding":"IL-17B induces resistance to paclitaxel in breast tumors through activation of the ERK1/2 pathway, leading to upregulation of anti-apoptotic BCL-2 family proteins; pharmacological blockade of ERK (PD98059) or anti-IL-17RB antibody abolished this chemoresistance in vivo.","method":"In vitro ERK1/2 signaling analysis, in vivo paclitaxel resistance model, anti-IL-17RB neutralizing antibody, MEK inhibitor PD98059","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods with defined pathway, in vivo validation, and pharmacological rescue","pmids":["29371916"],"is_preprint":false},{"year":2017,"finding":"IL-17B activates NF-κB, STAT3, and β-catenin pathways in mesenchymal stem cells, inducing stemness-related genes (Nanog, Sox2, Oct4) and causing MSCs to secrete soluble factors that promote gastric cancer cell proliferation and migration.","method":"Recombinant IL-17B treatment of MSCs, Western blot for pathway activation, conditioned medium experiments, proliferation and migration assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — single lab with multiple pathway readouts and functional co-culture experiments","pmids":["28145881"],"is_preprint":false},{"year":2018,"finding":"IL-17RB overexpression in lung cancer cells induces ERK phosphorylation, GSK3β inactivation, and β-catenin upregulation; IL-17RB also participates in IL-17B synthesis via ERK, forming a positive feedback loop that enhances invasion and metastasis.","method":"IL-17RB overexpression, in vitro invasion/migration assays, ERK/GSK3β/β-catenin pathway analysis, in vivo metastasis model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — single lab with multiple pathway and functional readouts including in vivo data","pmids":["29496538"],"is_preprint":false},{"year":2019,"finding":"IL-17B signals through a receptor complex composed of IL-17RA and IL-17RB to elicit type 2 cytokine secretion from innate type 2 lymphocytes, NKT, and CD4+ CRTH2+ Th2 cells in the human immune system, and can augment IL-33-driven type 2 responses.","method":"Receptor subunit requirement experiments with blocking antibodies, cytokine secretion assays from human lymphocyte subsets","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 — direct receptor identification with neutralizing antibodies and multiple human cell type readouts","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 TRAF6-mediated K63-linked ubiquitination of Beclin-1, thereby activating autophagy; ATG7 knockdown reversed IL-17B-induced CSC self-renewal.","method":"Sphere-formation assay, xenograft mouse model, co-immunoprecipitation of TRAF6-Beclin-1, ubiquitination assay, ATG7 siRNA knockdown, LC3 autophagy markers","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic pathway with co-IP, ubiquitination assay, genetic knockdown, and in vivo validation","pmids":["33649532"],"is_preprint":false},{"year":2021,"finding":"Tumor-derived IL-17B carried in extracellular vesicles activates pancreatic stellate cells (PSCs) and induces IL-17RB expression in PSCs; IL-17B/IL-17RB signaling increases oxidative phosphorylation and reduces mitochondrial turnover in PSCs, which then activate tumor cells via a feedback loop involving IL-6, increasing tumor oxidative phosphorylation and decreasing glycolysis.","method":"Extracellular vesicle isolation, IL-17RB overexpression in PSCs, co-injection xenograft model, metabolic flux analysis","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — single lab with EV-mediated signaling, metabolic readouts, and in vivo co-injection model","pmids":["34771503"],"is_preprint":false},{"year":2024,"finding":"Schwann-cell-secreted IL-17B acts in an autocrine manner by binding to IL-17RB on Schwann cells to promote macrophage recruitment to injured peripheral nerves; global or Schwann-cell-specific IL-17B deletion reduces macrophage infiltration, myelin clearance, and axon regeneration after peripheral nerve injury.","method":"Mlkl-/- and Sarm1-/- mouse models, global and conditional (Schwann-cell-specific) IL-17B knockout mice, peripheral nerve injury model, macrophage infiltration and myelin clearance quantification","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic loss-of-function models with defined cellular mechanism and functional phenotypic readouts","pmids":["38341853"],"is_preprint":false},{"year":2016,"finding":"IL-17B induces IL-8 gene and protein expression in human bronchial epithelial cells (but not lung fibroblasts) through activation of Akt, p38 MAPK, ERK, and NF-κB signaling pathways.","method":"Recombinant IL-17B treatment, RT-PCR, ELISA, Western blot for signaling pathway components in bronchial epithelial cells","journal":"Clinical immunology (Orlando, Fla.)","confidence":"Medium","confidence_rationale":"Tier 2 — single lab with multiple signaling pathway readouts and cell-type specificity demonstrated","pmids":["28039016"],"is_preprint":false},{"year":2010,"finding":"Recombinant human IL-17B inhibits endothelial cell-matrix adhesion and migration, and at higher concentrations substantially reduces tubule formation in a Matrigel assay, suggesting an anti-angiogenic function.","method":"In vitro cell adhesion assay, migration assay, Matrigel tubule formation assay with HECV endothelial cells","journal":"Journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, in vitro only, no in vivo validation or mechanistic pathway defined","pmids":["20467469"],"is_preprint":false}],"current_model":"IL-17B is a secreted cytokine that signals primarily through a receptor complex of IL-17RB (with IL-17RA as co-receptor for immune cells), activating ERK1/2, NF-κB, STAT3, and β-catenin pathways to promote TNF-α/IL-1β production from monocytes, type 2 cytokine responses from lymphocytes, cancer cell survival/invasion/chemoresistance, cancer stem cell autophagy via TRAF6-mediated Beclin-1 K63 ubiquitination, and macrophage recruitment to injured peripheral nerves through Schwann cell autocrine signaling."},"narrative":{"teleology":[{"year":2000,"claim":"Cloning of IL-17B established it as a distinct IL-17 family member that stimulates monocyte TNF-α/IL-1β production yet does not bind the canonical IL-17R, implying a separate receptor and a non-redundant pro-inflammatory function.","evidence":"Recombinant protein expression, FACS binding assay, and cytokine induction in THP-1 monocytic cells","pmids":["10639155"],"confidence":"High","gaps":["Cognate receptor not yet identified","No in vivo functional data","Downstream signaling pathway undefined"]},{"year":2002,"claim":"Expression mapping revealed IL-17B is prominently produced by neurons in the CNS and peripheral ganglia, expanding its potential functional scope beyond classical immune tissues.","evidence":"Northern blot, in situ hybridization, and immunohistochemistry in human and mouse neural tissues","pmids":["11738356"],"confidence":"High","gaps":["Neuronal function of IL-17B not tested","Receptor expression pattern in nervous system not characterized"]},{"year":2007,"claim":"In vivo studies demonstrated that IL-17B is a bona fide pro-inflammatory cytokine capable of exacerbating autoimmune arthritis, and that neutralizing IL-17B suppresses joint destruction, establishing disease relevance.","evidence":"Adoptive transfer of IL-17B-transduced CD4+ T cells and anti-IL-17B neutralizing antibody in the collagen-induced arthritis mouse model","pmids":["17982105"],"confidence":"High","gaps":["Direct receptor identity still unknown","Mechanism of action in joint tissue not elucidated"]},{"year":2015,"claim":"Identification of IL-17RB as the signaling receptor and ERK1/2 as the key downstream pathway resolved how IL-17B promotes cancer cell invasion and metastasis via chemokine induction (CCL20, CXCL1, IL-8).","evidence":"IL-17B/IL-17RB overexpression, ERK pathway analysis, anti-IL-17RB antibody blockade in pancreatic cancer xenograft model","pmids":["25732306"],"confidence":"High","gaps":["IL-17RA involvement as co-receptor not yet established","Structural basis of IL-17B–IL-17RB interaction unknown"]},{"year":2016,"claim":"IL-17B was shown to activate Akt, p38 MAPK, ERK, and NF-κB in bronchial epithelial cells to induce IL-8, broadening the pathway repertoire beyond ERK alone and demonstrating cell-type-specific responsiveness.","evidence":"Recombinant IL-17B treatment with pathway inhibitors and signaling readouts in human bronchial epithelial cells vs. fibroblasts","pmids":["28039016"],"confidence":"Medium","gaps":["Single-lab finding without independent replication","Receptor complex composition on epithelial cells not defined"]},{"year":2017,"claim":"Two studies established that IL-17B–ERK signaling drives chemoresistance in breast cancer (via BCL-2 upregulation) and activates NF-κB/STAT3/β-catenin stemness programs in mesenchymal stromal cells, revealing roles in therapy resistance and tumor microenvironment remodeling.","evidence":"ERK inhibitor and anti-IL-17RB antibody rescue of paclitaxel resistance in vivo; recombinant IL-17B treatment of MSCs with pathway and conditioned-medium assays","pmids":["29371916","28145881"],"confidence":"High","gaps":["Relative contribution of each pathway branch to chemoresistance not dissected","In vivo MSC–tumor interaction not validated with genetic models"]},{"year":2019,"claim":"Definition of IL-17RA–IL-17RB as the heterodimeric receptor complex on immune cells and demonstration that IL-17B elicits type 2 cytokine responses from ILC2s, NKT, and Th2 cells resolved how IL-17B engages adaptive and innate immunity.","evidence":"Blocking antibodies against IL-17RA and IL-17RB subunits, cytokine secretion assays from multiple human lymphocyte subsets","pmids":["30770417"],"confidence":"High","gaps":["Signaling adaptors downstream of IL-17RA/RB in lymphocytes not identified","Physiological contexts triggering IL-17B release in immunity unclear"]},{"year":2021,"claim":"Mechanistic dissection showed IL-17B promotes gastric cancer stem cell self-renewal through TRAF6-mediated K63-linked ubiquitination of Beclin-1 and autophagy activation, linking IL-17B signaling to the autophagy machinery for the first time.","evidence":"Co-immunoprecipitation, ubiquitination assay, ATG7 siRNA knockdown, sphere formation, and xenograft validation","pmids":["33649532"],"confidence":"High","gaps":["Whether TRAF6-Beclin-1 axis operates in non-cancer contexts unknown","Direct recruitment mechanism of TRAF6 to IL-17RB not defined"]},{"year":2021,"claim":"Tumor-derived IL-17B carried in extracellular vesicles was shown to reprogram pancreatic stellate cell metabolism toward oxidative phosphorylation, revealing a paracrine metabolic coupling between tumor and stroma through EV-mediated IL-17B delivery.","evidence":"EV isolation, IL-17RB modulation in stellate cells, metabolic flux analysis, co-injection xenograft","pmids":["34771503"],"confidence":"Medium","gaps":["EV-loading mechanism for IL-17B not characterized","In vivo metabolic reprogramming not confirmed by isotope tracing"]},{"year":2024,"claim":"Conditional knockout studies established that Schwann cell–derived IL-17B acts in an autocrine loop through IL-17RB to recruit macrophages after peripheral nerve injury, linking IL-17B to nerve repair and myelin clearance.","evidence":"Global and Schwann-cell-specific IL-17B knockout mice, peripheral nerve crush model with macrophage infiltration and axon regeneration quantification","pmids":["38341853"],"confidence":"High","gaps":["Downstream chemokines mediating macrophage recruitment by Schwann cells not fully defined","Whether IL-17B plays analogous roles in CNS demyelination untested"]},{"year":null,"claim":"No structural model of the IL-17B–IL-17RB–IL-17RA ternary complex exists, and the proximal signaling adaptors linking the receptor to TRAF6, ERK, and NF-κB remain incompletely mapped; a unified model integrating IL-17B's immunological, neural, and oncogenic functions is lacking.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of IL-17B or its receptor complex","Adaptor molecules connecting IL-17RB to TRAF6 and MAPK cascades not identified","Physiological triggers controlling IL-17B secretion in non-cancer settings unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,4,8,11]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,4,10,11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5,6,7,8,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,8]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,5,9]}],"complexes":[],"partners":["IL17RB","IL17RA","TRAF6","BECN1"],"other_free_text":[]},"mechanistic_narrative":"IL-17B is a secreted cytokine of the IL-17 family that signals through a receptor complex containing IL-17RB (and IL-17RA as co-receptor on immune cells) to activate ERK1/2, NF-κB, STAT3, Akt, p38 MAPK, and β-catenin pathways, driving pro-inflammatory cytokine and chemokine production in monocytes, epithelial cells, and mesenchymal stromal cells [PMID:10639155, PMID:28039016, PMID:28145881, PMID:30770417]. In the immune system, IL-17B stimulates TNF-α and IL-1β release from monocytes, elicits type 2 cytokine secretion from innate lymphoid cells, NKT cells, and Th2 cells, and exacerbates inflammatory arthritis in vivo [PMID:10639155, PMID:17982105, PMID:30770417]. In cancer, IL-17B–IL-17RB signaling promotes tumor invasion, chemoresistance via ERK-dependent upregulation of BCL-2 family proteins, and cancer stem cell self-renewal through TRAF6-mediated K63 ubiquitination of Beclin-1 and consequent autophagy activation [PMID:25732306, PMID:29371916, PMID:33649532]. In the peripheral nervous system, Schwann cell–derived IL-17B acts in an autocrine manner to recruit macrophages to injured nerves, facilitating myelin clearance and axon regeneration [PMID:38341853]."},"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":"17277128","id":"PMC_17277128","title":"The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17277128","citation_count":422,"is_preprint":false},{"pmid":"19330474","id":"PMC_19330474","title":"IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-gamma are not.","date":"2009","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/19330474","citation_count":352,"is_preprint":false},{"pmid":"11564763","id":"PMC_11564763","title":"Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types.","date":"2001","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11564763","citation_count":339,"is_preprint":false},{"pmid":"25421700","id":"PMC_25421700","title":"The IL-20 subfamily of cytokines--from host defence to tissue homeostasis.","date":"2014","source":"Nature reviews. 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neutralization of IL-17B significantly suppressed arthritis progression and bone destruction.\",\n      \"method\": \"In vitro cytokine induction assay, adoptive T cell transfer, bone marrow chimeric mice, anti-IL-17B neutralizing antibody treatment in CIA model\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vivo and in vitro methods with loss-of-function neutralization and defined phenotypic readouts\",\n      \"pmids\": [\"17982105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IL-17B and IL-17C are expressed in cartilage and chondrocytes during fracture healing and in the epiphyseal growth plate, with localization paralleling that of IL-17R and IL-17RL, suggesting a role in endochondral differentiation.\",\n      \"method\": \"Immunolocalization (immunohistochemistry) in fracture callus and growth plate\",\n      \"journal\": \"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single localization method without functional mechanistic follow-up\",\n      \"pmids\": [\"17827167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-17B–IL-17RB signaling activates the ERK1/2 pathway to upregulate CCL20, CXCL1, IL-8, and TFF1 chemokines, promoting pancreatic cancer cell invasion, macrophage and endothelial cell recruitment, and cancer cell survival at distant sites; anti-IL-17RB antibody blocked tumor metastasis in a xenograft model.\",\n      \"method\": \"Ex vivo experiments with IL-17B/IL-17RB overexpression, ERK1/2 pathway analysis, xenograft mouse model, monoclonal antibody blockade\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including pathway analysis, in vivo xenograft, and antibody blockade with defined molecular mechanism\",\n      \"pmids\": [\"25732306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-17B induces resistance to paclitaxel in breast tumors through activation of the ERK1/2 pathway, leading to upregulation of anti-apoptotic BCL-2 family proteins; pharmacological blockade of ERK (PD98059) or anti-IL-17RB antibody abolished this chemoresistance in vivo.\",\n      \"method\": \"In vitro ERK1/2 signaling analysis, in vivo paclitaxel resistance model, anti-IL-17RB neutralizing antibody, MEK inhibitor PD98059\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods with defined pathway, in vivo validation, and pharmacological rescue\",\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, inducing stemness-related genes (Nanog, Sox2, Oct4) and causing MSCs to secrete soluble factors that promote gastric cancer cell proliferation and migration.\",\n      \"method\": \"Recombinant IL-17B treatment of MSCs, Western blot for pathway activation, conditioned medium experiments, proliferation and migration assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab with multiple pathway readouts and functional co-culture experiments\",\n      \"pmids\": [\"28145881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-17RB overexpression in lung cancer cells induces ERK phosphorylation, GSK3β inactivation, and β-catenin upregulation; IL-17RB also participates in IL-17B synthesis via ERK, forming a positive feedback loop that enhances invasion and metastasis.\",\n      \"method\": \"IL-17RB overexpression, in vitro invasion/migration assays, ERK/GSK3β/β-catenin pathway analysis, in vivo metastasis model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab with multiple pathway and functional readouts including in vivo data\",\n      \"pmids\": [\"29496538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17B signals through a receptor complex composed of IL-17RA and IL-17RB to elicit type 2 cytokine secretion from innate type 2 lymphocytes, NKT, and CD4+ CRTH2+ Th2 cells in the human immune system, and can augment IL-33-driven type 2 responses.\",\n      \"method\": \"Receptor subunit requirement experiments with blocking antibodies, cytokine secretion assays from human lymphocyte subsets\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct receptor identification with neutralizing antibodies and multiple human cell type readouts\",\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 TRAF6-mediated K63-linked ubiquitination of Beclin-1, thereby activating autophagy; ATG7 knockdown reversed IL-17B-induced CSC self-renewal.\",\n      \"method\": \"Sphere-formation assay, xenograft mouse model, co-immunoprecipitation of TRAF6-Beclin-1, ubiquitination assay, ATG7 siRNA knockdown, LC3 autophagy markers\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic pathway with co-IP, ubiquitination assay, genetic knockdown, and in vivo validation\",\n      \"pmids\": [\"33649532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tumor-derived IL-17B carried in extracellular vesicles activates pancreatic stellate cells (PSCs) and induces IL-17RB expression in PSCs; IL-17B/IL-17RB signaling increases oxidative phosphorylation and reduces mitochondrial turnover in PSCs, which then activate tumor cells via a feedback loop involving IL-6, increasing tumor oxidative phosphorylation and decreasing glycolysis.\",\n      \"method\": \"Extracellular vesicle isolation, IL-17RB overexpression in PSCs, co-injection xenograft model, metabolic flux analysis\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab with EV-mediated signaling, metabolic readouts, and in vivo co-injection model\",\n      \"pmids\": [\"34771503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Schwann-cell-secreted IL-17B acts in an autocrine manner by binding to IL-17RB on Schwann cells to promote macrophage recruitment to injured peripheral nerves; global or Schwann-cell-specific IL-17B deletion reduces macrophage infiltration, myelin clearance, and axon regeneration after peripheral nerve injury.\",\n      \"method\": \"Mlkl-/- and Sarm1-/- mouse models, global and conditional (Schwann-cell-specific) IL-17B knockout mice, peripheral nerve injury model, macrophage infiltration and myelin clearance quantification\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic loss-of-function models with defined cellular mechanism and functional phenotypic readouts\",\n      \"pmids\": [\"38341853\"],\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) through activation of Akt, p38 MAPK, ERK, and NF-κB signaling pathways.\",\n      \"method\": \"Recombinant IL-17B treatment, RT-PCR, ELISA, Western blot for signaling pathway components in bronchial epithelial cells\",\n      \"journal\": \"Clinical immunology (Orlando, Fla.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab with multiple signaling pathway readouts and cell-type specificity demonstrated\",\n      \"pmids\": [\"28039016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Recombinant human IL-17B inhibits endothelial cell-matrix adhesion and migration, and at higher concentrations substantially reduces tubule formation in a Matrigel assay, suggesting an anti-angiogenic function.\",\n      \"method\": \"In vitro cell adhesion assay, migration assay, Matrigel tubule formation assay with HECV endothelial cells\",\n      \"journal\": \"Journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, in vitro only, no in vivo validation or mechanistic pathway defined\",\n      \"pmids\": [\"20467469\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-17B is a secreted cytokine that signals primarily through a receptor complex of IL-17RB (with IL-17RA as co-receptor for immune cells), activating ERK1/2, NF-κB, STAT3, and β-catenin pathways to promote TNF-α/IL-1β production from monocytes, type 2 cytokine responses from lymphocytes, cancer cell survival/invasion/chemoresistance, cancer stem cell autophagy via TRAF6-mediated Beclin-1 K63 ubiquitination, and macrophage recruitment to injured peripheral nerves through Schwann cell autocrine signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL-17B is a secreted cytokine of the IL-17 family that signals through a receptor complex containing IL-17RB (and IL-17RA as co-receptor on immune cells) to activate ERK1/2, NF-κB, STAT3, Akt, p38 MAPK, and β-catenin pathways, driving pro-inflammatory cytokine and chemokine production in monocytes, epithelial cells, and mesenchymal stromal cells [PMID:10639155, PMID:28039016, PMID:28145881, PMID:30770417]. In the immune system, IL-17B stimulates TNF-α and IL-1β release from monocytes, elicits type 2 cytokine secretion from innate lymphoid cells, NKT cells, and Th2 cells, and exacerbates inflammatory arthritis in vivo [PMID:10639155, PMID:17982105, PMID:30770417]. In cancer, IL-17B–IL-17RB signaling promotes tumor invasion, chemoresistance via ERK-dependent upregulation of BCL-2 family proteins, and cancer stem cell self-renewal through TRAF6-mediated K63 ubiquitination of Beclin-1 and consequent autophagy activation [PMID:25732306, PMID:29371916, PMID:33649532]. In the peripheral nervous system, Schwann cell–derived IL-17B acts in an autocrine manner to recruit macrophages to injured nerves, facilitating myelin clearance and axon regeneration [PMID:38341853].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Cloning of IL-17B established it as a distinct IL-17 family member that stimulates monocyte TNF-α/IL-1β production yet does not bind the canonical IL-17R, implying a separate receptor and a non-redundant pro-inflammatory function.\",\n      \"evidence\": \"Recombinant protein expression, FACS binding assay, and cytokine induction in THP-1 monocytic cells\",\n      \"pmids\": [\"10639155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cognate receptor not yet identified\", \"No in vivo functional data\", \"Downstream signaling pathway undefined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Expression mapping revealed IL-17B is prominently produced by neurons in the CNS and peripheral ganglia, expanding its potential functional scope beyond classical immune tissues.\",\n      \"evidence\": \"Northern blot, in situ hybridization, and immunohistochemistry in human and mouse neural tissues\",\n      \"pmids\": [\"11738356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neuronal function of IL-17B not tested\", \"Receptor expression pattern in nervous system not characterized\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"In vivo studies demonstrated that IL-17B is a bona fide pro-inflammatory cytokine capable of exacerbating autoimmune arthritis, and that neutralizing IL-17B suppresses joint destruction, establishing disease relevance.\",\n      \"evidence\": \"Adoptive transfer of IL-17B-transduced CD4+ T cells and anti-IL-17B neutralizing antibody in the collagen-induced arthritis mouse model\",\n      \"pmids\": [\"17982105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct receptor identity still unknown\", \"Mechanism of action in joint tissue not elucidated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of IL-17RB as the signaling receptor and ERK1/2 as the key downstream pathway resolved how IL-17B promotes cancer cell invasion and metastasis via chemokine induction (CCL20, CXCL1, IL-8).\",\n      \"evidence\": \"IL-17B/IL-17RB overexpression, ERK pathway analysis, anti-IL-17RB antibody blockade in pancreatic cancer xenograft model\",\n      \"pmids\": [\"25732306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"IL-17RA involvement as co-receptor not yet established\", \"Structural basis of IL-17B–IL-17RB interaction unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"IL-17B was shown to activate Akt, p38 MAPK, ERK, and NF-κB in bronchial epithelial cells to induce IL-8, broadening the pathway repertoire beyond ERK alone and demonstrating cell-type-specific responsiveness.\",\n      \"evidence\": \"Recombinant IL-17B treatment with pathway inhibitors and signaling readouts in human bronchial epithelial cells vs. fibroblasts\",\n      \"pmids\": [\"28039016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without independent replication\", \"Receptor complex composition on epithelial cells not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two studies established that IL-17B–ERK signaling drives chemoresistance in breast cancer (via BCL-2 upregulation) and activates NF-κB/STAT3/β-catenin stemness programs in mesenchymal stromal cells, revealing roles in therapy resistance and tumor microenvironment remodeling.\",\n      \"evidence\": \"ERK inhibitor and anti-IL-17RB antibody rescue of paclitaxel resistance in vivo; recombinant IL-17B treatment of MSCs with pathway and conditioned-medium assays\",\n      \"pmids\": [\"29371916\", \"28145881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each pathway branch to chemoresistance not dissected\", \"In vivo MSC–tumor interaction not validated with genetic models\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Definition of IL-17RA–IL-17RB as the heterodimeric receptor complex on immune cells and demonstration that IL-17B elicits type 2 cytokine responses from ILC2s, NKT, and Th2 cells resolved how IL-17B engages adaptive and innate immunity.\",\n      \"evidence\": \"Blocking antibodies against IL-17RA and IL-17RB subunits, cytokine secretion assays from multiple human lymphocyte subsets\",\n      \"pmids\": [\"30770417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling adaptors downstream of IL-17RA/RB in lymphocytes not identified\", \"Physiological contexts triggering IL-17B release in immunity unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mechanistic dissection showed IL-17B promotes gastric cancer stem cell self-renewal through TRAF6-mediated K63-linked ubiquitination of Beclin-1 and autophagy activation, linking IL-17B signaling to the autophagy machinery for the first time.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assay, ATG7 siRNA knockdown, sphere formation, and xenograft validation\",\n      \"pmids\": [\"33649532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRAF6-Beclin-1 axis operates in non-cancer contexts unknown\", \"Direct recruitment mechanism of TRAF6 to IL-17RB not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tumor-derived IL-17B carried in extracellular vesicles was shown to reprogram pancreatic stellate cell metabolism toward oxidative phosphorylation, revealing a paracrine metabolic coupling between tumor and stroma through EV-mediated IL-17B delivery.\",\n      \"evidence\": \"EV isolation, IL-17RB modulation in stellate cells, metabolic flux analysis, co-injection xenograft\",\n      \"pmids\": [\"34771503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"EV-loading mechanism for IL-17B not characterized\", \"In vivo metabolic reprogramming not confirmed by isotope tracing\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Conditional knockout studies established that Schwann cell–derived IL-17B acts in an autocrine loop through IL-17RB to recruit macrophages after peripheral nerve injury, linking IL-17B to nerve repair and myelin clearance.\",\n      \"evidence\": \"Global and Schwann-cell-specific IL-17B knockout mice, peripheral nerve crush model with macrophage infiltration and axon regeneration quantification\",\n      \"pmids\": [\"38341853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream chemokines mediating macrophage recruitment by Schwann cells not fully defined\", \"Whether IL-17B plays analogous roles in CNS demyelination untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No structural model of the IL-17B–IL-17RB–IL-17RA ternary complex exists, and the proximal signaling adaptors linking the receptor to TRAF6, ERK, and NF-κB remain incompletely mapped; a unified model integrating IL-17B's immunological, neural, and oncogenic functions is lacking.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of IL-17B or its receptor complex\", \"Adaptor molecules connecting IL-17RB to TRAF6 and MAPK cascades not identified\", \"Physiological triggers controlling IL-17B secretion in non-cancer settings unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 4, 8, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 4, 10, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 6, 7, 8, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IL17RB\",\n      \"IL17RA\",\n      \"TRAF6\",\n      \"BECN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}