{"gene":"IL37","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2002,"finding":"IL-1F7b (IL-37) is processed by caspase-1 at a predicted propeptide cleavage site to generate mature IL-1F7b; caspase-4 can also cleave IL-1F7b but inefficiently; other caspases and Granzyme-B do not cleave it. Adenovirus-mediated expression in HEK293 cells confirmed in situ processing and secretion of mature IL-1F7b.","method":"In vitro caspase cleavage assay; adenovirus-mediated expression in HEK293 cells","journal":"Cytokine","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro enzymatic assay with multiple caspases tested, confirmed in cellular expression system, replicated conceptually by independent labs","pmids":["12096920"],"is_preprint":false},{"year":2002,"finding":"Both pro- and mature IL-1F7b bind to soluble IL-18Rα-Fc but not to soluble IL-1R-Fc or ST2R-Fc fusion proteins; mature IL-1F7b binds IL-18Rα with higher affinity than the pro-form, though both affinities are significantly lower than IL-18. Mature IL-1F7b does not induce IFN-γ production by KG1a cells.","method":"Binding screen with soluble receptor-Fc fusion proteins; functional IFN-γ induction assay with KG1a cells","journal":"Cytokine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding assay with multiple receptor fusion proteins as controls, functional assay, replicated by independent group (PMID:12381835)","pmids":["12096920","12381835"],"is_preprint":false},{"year":2002,"finding":"Pro- and mature IL-1F7b form homodimers with association constants of ~4 µM and ~5 nM, respectively, indicating that caspase-1 processing dramatically increases homodimerization affinity.","method":"Biophysical binding/dimerization assay (association constant measurement)","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative binding assay in single lab with two protein forms compared","pmids":["12096920"],"is_preprint":false},{"year":2002,"finding":"IL-1F7b fails to recruit IL-18Rβ to form a functionally active ternary complex with IL-18Rα, unlike IL-18 which recruits IL-18Rβ. This failure to recruit IL-18Rβ explains the lack of IL-18 agonist activity.","method":"Chemical cross-linking followed by SDS-PAGE analysis of receptor complex formation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct chemical cross-linking experiment with clear mechanistic interpretation, replicated conceptually in multiple studies","pmids":["12381835"],"is_preprint":false},{"year":2002,"finding":"IL-1F7b forms a high molecular weight complex with IL-18-binding protein (IL-18BP) detected by chemical cross-linking. This IL-1F7b/IL-18BP complex enhances the ability of IL-18BP to inhibit IL-18-induced IFN-γ production by ~25–30% in a human NK cell line and in PBMCs, primarily at limiting concentrations of IL-18BP.","method":"Chemical cross-linking and SDS-PAGE; functional IFN-γ inhibition assay in NK cell line and PBMCs","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct complex detection by cross-linking plus functional readout in two independent cell systems (NK line and primary PBMCs)","pmids":["12381835"],"is_preprint":false},{"year":2002,"finding":"IL-1F7b protein is localized in discrete cell populations including plasma cells and tumor cells, as determined by immunohistochemical staining.","method":"Immunohistochemistry on human tissue/cells","journal":"Cytokine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (IHC), single lab, no functional consequence linked","pmids":["12096920"],"is_preprint":false},{"year":2002,"finding":"IL-1F7 (IL-37) is localized in human peripheral monocytic cells by immunohistochemical staining.","method":"Immunohistochemistry on human peripheral monocytic cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (IHC), single lab, no functional consequence linked","pmids":["12381835"],"is_preprint":false},{"year":2003,"finding":"Intratumoral adenovirus-mediated delivery of IL-1H4 (IL-1F7/IL-37) suppresses established fibrosarcoma growth in mice in an IL-12-, IFN-γ-, and Fas-ligand-dependent manner, but the effect is independent of NKT cells. Anti-tumor activity is abrogated in nude and SCID mice, indicating a requirement for adaptive immunity.","method":"Genetic epistasis using KO mice (IL-12-/-, IFN-γ-/-, FasL-/-, NKT-deficient, nude, SCID); adenovirus-mediated intratumoral gene transfer","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis across multiple KO strains in a single lab, clear mechanistic pathway placement","pmids":["12496389"],"is_preprint":false},{"year":2011,"finding":"IL-37 localizes to the nucleus (in addition to its extracellular functions), analogous to IL-1α and IL-33, suggesting a receptor-independent intranuclear role in regulating inflammation.","method":"Nuclear localization reported in review based on cited experimental data (implied from localization studies)","journal":"European cytokine network","confidence":"Low","confidence_rationale":"Tier 3 / Weak — described in a review citing prior experimental work; method details not specified in abstract","pmids":["22047735"],"is_preprint":false},{"year":2016,"finding":"In transgenic mice expressing human IL-37b, IL-37 attenuates NREMS increases induced by IL-1β or LPS (responses ~4-fold greater in WT than IL-37-transgenic mice), demonstrating that IL-37 suppresses inflammation-driven sleep responses in vivo.","method":"In vivo sleep recording in IL-37 transgenic vs. wild-type mice; pharmacological challenge with LPS and IL-1β; influenza virus infection model","journal":"Neurobiology of sleep and circadian rhythms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vivo functional comparison using transgenic model with multiple challenge conditions in single lab","pmids":["28070566"],"is_preprint":false},{"year":2024,"finding":"Computational modeling (AlphaFold2 multimer + molecular dynamics) shows that IL-37 complexes with IL-18Rα adopt altered receptor conformations that can accommodate IL-37 in dimeric form but prevent IL-18Rβ recruitment; the N-terminal loop of IL-37 is pivotal in modulating receptor dynamics, and glycosyl chains on receptor residue N297 act as a steric block against IL-37's N-terminal loop. IL-37–IL-18BP interactions suggest a binding mode distinct from IL-18–IL-18BP, indicating an alternative anti-inflammatory mechanism.","method":"Homology modeling, AlphaFold2 multimer prediction, classical molecular dynamics simulations","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no experimental validation, preprint","pmids":["bio_10.1101_2024.09.21.613817"],"is_preprint":true}],"current_model":"IL-37 (IL-1F7) is an anti-inflammatory IL-1 family cytokine processed intracellularly by caspase-1 (and to a lesser extent caspase-4) to generate a mature form that homodimerizes with high affinity; extracellularly, it binds IL-18Rα without recruiting IL-18Rβ and thus cannot form a functional ternary signaling complex, while also forming a complex with IL-18BP that cooperatively enhances IL-18 neutralization; additionally, IL-37 translocates to the nucleus for receptor-independent transcriptional regulation of inflammation, and in vivo expression of IL-37 suppresses pro-inflammatory cytokine-driven responses including sleep alterations and tumor growth via an IL-12/IFN-γ/FasL-dependent adaptive immune pathway."},"narrative":{"mechanistic_narrative":"IL-37 (IL-1F7) is an anti-inflammatory IL-1 family cytokine that restrains pro-inflammatory responses through both receptor-dependent and intracellular mechanisms [PMID:12096920, PMID:12381835, PMID:12496389]. It is synthesized as a precursor and processed by caspase-1 at a propeptide cleavage site to generate a mature form, with caspase-4 contributing inefficiently and other caspases unable to cleave it [PMID:12096920]; this processing markedly increases its homodimerization affinity [PMID:12096920]. Both pro- and mature IL-37 bind IL-18Rα but not IL-1R or ST2R, yet IL-37 fails to recruit IL-18Rβ into a functional ternary complex, accounting for its lack of IL-18-like agonist activity [PMID:12096920, PMID:12381835]. IL-37 additionally forms a high molecular weight complex with IL-18-binding protein that enhances IL-18BP-mediated neutralization of IL-18-induced IFN-γ [PMID:12381835]. In vivo, adenoviral delivery of IL-37 suppresses fibrosarcoma growth through an IL-12-, IFN-γ-, and Fas-ligand-dependent adaptive immune pathway [PMID:12496389], and transgenic expression of human IL-37 attenuates inflammation-driven sleep responses elicited by IL-1β or LPS [PMID:28070566].","teleology":[{"year":2002,"claim":"Established how the IL-37 precursor is converted to a mature cytokine, identifying caspase-1 as the principal processing enzyme and defining the maturation step that governs its activity.","evidence":"In vitro caspase cleavage assays against multiple caspases plus adenoviral expression in HEK293 cells","pmids":["12096920"],"confidence":"High","gaps":["Physiological trigger and cellular context of caspase-1 processing not defined","Whether mature form is the dominant secreted species in vivo not established"]},{"year":2002,"claim":"Defined IL-37's receptor selectivity, showing it engages IL-18Rα with affinity weaker than IL-18 and does not bind IL-1R or ST2R, framing it as an IL-18Rα-directed ligand without agonist output.","evidence":"Binding screen with soluble receptor-Fc fusions and IFN-γ induction assay in KG1a cells","pmids":["12096920","12381835"],"confidence":"High","gaps":["Affinity for IL-18Rα is low, leaving physiological relevance of this binding open","No downstream signaling readout established for IL-37 binding"]},{"year":2002,"claim":"Showed that caspase-1 processing dramatically increases homodimerization affinity, linking maturation to a defined biophysical state of the cytokine.","evidence":"Association constant measurement comparing pro- and mature forms","pmids":["12096920"],"confidence":"Medium","gaps":["Functional consequence of homodimerization not resolved","Single-lab biophysical measurement without orthogonal structural confirmation"]},{"year":2002,"claim":"Explained why IL-37 lacks IL-18 agonist activity by demonstrating its failure to recruit IL-18Rβ into the ternary signaling complex.","evidence":"Chemical cross-linking and SDS-PAGE analysis of receptor complex formation","pmids":["12381835"],"confidence":"High","gaps":["Whether IL-18Rα engagement actively antagonizes IL-18 signaling not shown","Structural basis of failed co-receptor recruitment not resolved experimentally"]},{"year":2002,"claim":"Identified a second anti-inflammatory mechanism in which IL-37 complexes with IL-18BP to cooperatively enhance IL-18 neutralization.","evidence":"Chemical cross-linking plus IFN-γ inhibition assays in an NK cell line and PBMCs","pmids":["12381835"],"confidence":"High","gaps":["Enhancement is modest (~25-30%) and concentration-dependent","Stoichiometry and architecture of the IL-37/IL-18BP complex not determined"]},{"year":2003,"claim":"Placed IL-37 in an in vivo anti-tumor pathway, showing its effect requires IL-12, IFN-γ, Fas-ligand, and intact adaptive immunity.","evidence":"Genetic epistasis across IL-12-/-, IFN-γ-/-, FasL-/-, NKT-deficient, nude, and SCID mice with intratumoral adenoviral gene transfer","pmids":["12496389"],"confidence":"Medium","gaps":["Mechanistic link between IL-37 expression and IL-12/IFN-γ/FasL induction not defined","Reliance on adenoviral overexpression rather than endogenous IL-37"]},{"year":2011,"claim":"Raised the possibility of a receptor-independent intranuclear role for IL-37 by reporting nuclear localization analogous to IL-1α and IL-33.","evidence":"Nuclear localization described in a review citing prior experimental work","pmids":["22047735"],"confidence":"Low","gaps":["Reported in review without primary method detail","No nuclear transcriptional target or partner identified"]},{"year":2016,"claim":"Demonstrated an in vivo anti-inflammatory function by showing IL-37 attenuates inflammation-driven sleep responses triggered by IL-1β or LPS.","evidence":"Sleep recording in human IL-37b transgenic versus wild-type mice with LPS, IL-1β, and influenza challenge","pmids":["28070566"],"confidence":"Medium","gaps":["Molecular pathway connecting IL-37 to dampened NREMS responses not mapped","Relies on human transgene in mouse background"]},{"year":2024,"claim":"Proposed a structural rationale for IL-37's failure to recruit IL-18Rβ, implicating the N-terminal loop and an N297 glycan steric block, and a distinct IL-37/IL-18BP binding mode.","evidence":"Homology modeling, AlphaFold2 multimer prediction, and molecular dynamics simulations (preprint)","pmids":["bio_10.1101_2024.09.21.613817"],"confidence":"Low","gaps":["Computational prediction with no experimental validation","Predicted N-terminal loop and glycan roles not tested by mutagenesis"]},{"year":null,"claim":"The signaling output of IL-37 engagement of IL-18Rα and the molecular basis of its proposed intranuclear transcriptional role remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No intracellular signaling effector identified for IL-37 receptor binding","No nuclear binding partner or target gene established","Endogenous (non-overexpression) anti-inflammatory mechanism not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,7]}],"complexes":[],"partners":["IL18R1","IL18BP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NZH6","full_name":"Interleukin-37","aliases":["FIL1 zeta","IL-1X","Interleukin-1 family member 7","IL-1F7","Interleukin-1 homolog 4","IL-1H","IL-1H4","Interleukin-1 zeta","IL-1 zeta","Interleukin-1-related protein","IL-1RP1"],"length_aa":218,"mass_kda":24.1,"function":"Immune regulatory cytokine that acts as a suppressor of innate inflammatory and immune responses involved in curbing excessive inflammation. Signaling can occur via two mechanisms, intracellularly through nuclear translocation with SMAD3 and extracellularly after secretion and binding to its receptor composed of IL18R1 and IL18RAP. Suppresses, or reduces, pro-inflammatory cytokine production, including IL1A and IL6, as well as CCL12, CSF1, CSF2, CXCL13, IL1B, IL23A and IL1RN, but spares anti-inflammatory cytokines. Inhibits dendritic cell activation","subcellular_location":"Cytoplasm, cytosol; Nucleus; Secreted","url":"https://www.uniprot.org/uniprotkb/Q9NZH6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL37","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/IL37","total_profiled":1310},"omim":[{"mim_id":"619398","title":"INFLAMMATORY BOWEL DISEASE (INFANTILE ULCERATIVE COLITIS) 31, AUTOSOMAL RECESSIVE; IBD31","url":"https://www.omim.org/entry/619398"},{"mim_id":"615296","title":"INTERLEUKIN 1 FAMILY, MEMBER 10; IL1F10","url":"https://www.omim.org/entry/615296"},{"mim_id":"605542","title":"INTERLEUKIN 36, GAMMA; IL36G","url":"https://www.omim.org/entry/605542"},{"mim_id":"605510","title":"INTERLEUKIN 37; IL37","url":"https://www.omim.org/entry/605510"},{"mim_id":"605509","title":"INTERLEUKIN 36, ALPHA; IL36A","url":"https://www.omim.org/entry/605509"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"skin 1","ntpm":114.2}],"url":"https://www.proteinatlas.org/search/IL37"},"hgnc":{"alias_symbol":["FIL1","FIL1Z","FIL1(ZETA)","IL-1H4","IL-1RP1","IL-1F7"],"prev_symbol":["IL1F7"]},"alphafold":{"accession":"Q9NZH6","domains":[{"cath_id":"2.80.10.50","chopping":"59-206","consensus_level":"high","plddt":94.8411,"start":59,"end":206}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZH6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZH6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZH6-F1-predicted_aligned_error_v6.png","plddt_mean":81.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL37","jax_strain_url":"https://www.jax.org/strain/search?query=IL37"},"sequence":{"accession":"Q9NZH6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NZH6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NZH6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZH6"}},"corpus_meta":[{"pmid":"22047735","id":"PMC_22047735","title":"IL-37: 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Profiling of Inflammatory Factors Revealed That Growth Differentiation Factor-15 Is an Indicator of Disease Severity in COVID-19 Patients.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34335566","citation_count":29,"is_preprint":false},{"pmid":"21072596","id":"PMC_21072596","title":"Analysis on the interaction between IL-1F7 gene and environmental factors on patients with ankylosing spondylitis: a case-only study.","date":"2010","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/21072596","citation_count":20,"is_preprint":false},{"pmid":"27982737","id":"PMC_27982737","title":"IL-37 a New IL-1 Family Member Emerges as a Key Suppressor of Asthma Mediated by Mast Cells.","date":"2016","source":"Immunological investigations","url":"https://pubmed.ncbi.nlm.nih.gov/27982737","citation_count":15,"is_preprint":false},{"pmid":"28070566","id":"PMC_28070566","title":"Interleukin 37 expression in mice alters sleep responses to 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IL37","date":"2024-09-24","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.21.613817","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13098,"output_tokens":2562,"usd":0.038862,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9838,"output_tokens":2889,"usd":0.060707,"stage2_stop_reason":"end_turn"},"total_usd":0.099569,"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\": 2002,\n      \"finding\": \"IL-1F7b (IL-37) is processed by caspase-1 at a predicted propeptide cleavage site to generate mature IL-1F7b; caspase-4 can also cleave IL-1F7b but inefficiently; other caspases and Granzyme-B do not cleave it. Adenovirus-mediated expression in HEK293 cells confirmed in situ processing and secretion of mature IL-1F7b.\",\n      \"method\": \"In vitro caspase cleavage assay; adenovirus-mediated expression in HEK293 cells\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro enzymatic assay with multiple caspases tested, confirmed in cellular expression system, replicated conceptually by independent labs\",\n      \"pmids\": [\"12096920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Both pro- and mature IL-1F7b bind to soluble IL-18Rα-Fc but not to soluble IL-1R-Fc or ST2R-Fc fusion proteins; mature IL-1F7b binds IL-18Rα with higher affinity than the pro-form, though both affinities are significantly lower than IL-18. Mature IL-1F7b does not induce IFN-γ production by KG1a cells.\",\n      \"method\": \"Binding screen with soluble receptor-Fc fusion proteins; functional IFN-γ induction assay with KG1a cells\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding assay with multiple receptor fusion proteins as controls, functional assay, replicated by independent group (PMID:12381835)\",\n      \"pmids\": [\"12096920\", \"12381835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Pro- and mature IL-1F7b form homodimers with association constants of ~4 µM and ~5 nM, respectively, indicating that caspase-1 processing dramatically increases homodimerization affinity.\",\n      \"method\": \"Biophysical binding/dimerization assay (association constant measurement)\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative binding assay in single lab with two protein forms compared\",\n      \"pmids\": [\"12096920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IL-1F7b fails to recruit IL-18Rβ to form a functionally active ternary complex with IL-18Rα, unlike IL-18 which recruits IL-18Rβ. This failure to recruit IL-18Rβ explains the lack of IL-18 agonist activity.\",\n      \"method\": \"Chemical cross-linking followed by SDS-PAGE analysis of receptor complex formation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct chemical cross-linking experiment with clear mechanistic interpretation, replicated conceptually in multiple studies\",\n      \"pmids\": [\"12381835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IL-1F7b forms a high molecular weight complex with IL-18-binding protein (IL-18BP) detected by chemical cross-linking. This IL-1F7b/IL-18BP complex enhances the ability of IL-18BP to inhibit IL-18-induced IFN-γ production by ~25–30% in a human NK cell line and in PBMCs, primarily at limiting concentrations of IL-18BP.\",\n      \"method\": \"Chemical cross-linking and SDS-PAGE; functional IFN-γ inhibition assay in NK cell line and PBMCs\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct complex detection by cross-linking plus functional readout in two independent cell systems (NK line and primary PBMCs)\",\n      \"pmids\": [\"12381835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IL-1F7b protein is localized in discrete cell populations including plasma cells and tumor cells, as determined by immunohistochemical staining.\",\n      \"method\": \"Immunohistochemistry on human tissue/cells\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (IHC), single lab, no functional consequence linked\",\n      \"pmids\": [\"12096920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IL-1F7 (IL-37) is localized in human peripheral monocytic cells by immunohistochemical staining.\",\n      \"method\": \"Immunohistochemistry on human peripheral monocytic cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (IHC), single lab, no functional consequence linked\",\n      \"pmids\": [\"12381835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Intratumoral adenovirus-mediated delivery of IL-1H4 (IL-1F7/IL-37) suppresses established fibrosarcoma growth in mice in an IL-12-, IFN-γ-, and Fas-ligand-dependent manner, but the effect is independent of NKT cells. Anti-tumor activity is abrogated in nude and SCID mice, indicating a requirement for adaptive immunity.\",\n      \"method\": \"Genetic epistasis using KO mice (IL-12-/-, IFN-γ-/-, FasL-/-, NKT-deficient, nude, SCID); adenovirus-mediated intratumoral gene transfer\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis across multiple KO strains in a single lab, clear mechanistic pathway placement\",\n      \"pmids\": [\"12496389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-37 localizes to the nucleus (in addition to its extracellular functions), analogous to IL-1α and IL-33, suggesting a receptor-independent intranuclear role in regulating inflammation.\",\n      \"method\": \"Nuclear localization reported in review based on cited experimental data (implied from localization studies)\",\n      \"journal\": \"European cytokine network\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — described in a review citing prior experimental work; method details not specified in abstract\",\n      \"pmids\": [\"22047735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In transgenic mice expressing human IL-37b, IL-37 attenuates NREMS increases induced by IL-1β or LPS (responses ~4-fold greater in WT than IL-37-transgenic mice), demonstrating that IL-37 suppresses inflammation-driven sleep responses in vivo.\",\n      \"method\": \"In vivo sleep recording in IL-37 transgenic vs. wild-type mice; pharmacological challenge with LPS and IL-1β; influenza virus infection model\",\n      \"journal\": \"Neurobiology of sleep and circadian rhythms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vivo functional comparison using transgenic model with multiple challenge conditions in single lab\",\n      \"pmids\": [\"28070566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Computational modeling (AlphaFold2 multimer + molecular dynamics) shows that IL-37 complexes with IL-18Rα adopt altered receptor conformations that can accommodate IL-37 in dimeric form but prevent IL-18Rβ recruitment; the N-terminal loop of IL-37 is pivotal in modulating receptor dynamics, and glycosyl chains on receptor residue N297 act as a steric block against IL-37's N-terminal loop. IL-37–IL-18BP interactions suggest a binding mode distinct from IL-18–IL-18BP, indicating an alternative anti-inflammatory mechanism.\",\n      \"method\": \"Homology modeling, AlphaFold2 multimer prediction, classical molecular dynamics simulations\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no experimental validation, preprint\",\n      \"pmids\": [\"bio_10.1101_2024.09.21.613817\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"IL-37 (IL-1F7) is an anti-inflammatory IL-1 family cytokine processed intracellularly by caspase-1 (and to a lesser extent caspase-4) to generate a mature form that homodimerizes with high affinity; extracellularly, it binds IL-18Rα without recruiting IL-18Rβ and thus cannot form a functional ternary signaling complex, while also forming a complex with IL-18BP that cooperatively enhances IL-18 neutralization; additionally, IL-37 translocates to the nucleus for receptor-independent transcriptional regulation of inflammation, and in vivo expression of IL-37 suppresses pro-inflammatory cytokine-driven responses including sleep alterations and tumor growth via an IL-12/IFN-γ/FasL-dependent adaptive immune pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL-37 (IL-1F7) is an anti-inflammatory IL-1 family cytokine that restrains pro-inflammatory responses through both receptor-dependent and intracellular mechanisms [#1, #7]. It is synthesized as a precursor and processed by caspase-1 at a propeptide cleavage site to generate a mature form, with caspase-4 contributing inefficiently and other caspases unable to cleave it [#0]; this processing markedly increases its homodimerization affinity [#2]. Both pro- and mature IL-37 bind IL-18R\\u03b1 but not IL-1R or ST2R, yet IL-37 fails to recruit IL-18R\\u03b2 into a functional ternary complex, accounting for its lack of IL-18-like agonist activity [#1, #3]. IL-37 additionally forms a high molecular weight complex with IL-18-binding protein that enhances IL-18BP-mediated neutralization of IL-18-induced IFN-\\u03b3 [#4]. In vivo, adenoviral delivery of IL-37 suppresses fibrosarcoma growth through an IL-12-, IFN-\\u03b3-, and Fas-ligand-dependent adaptive immune pathway [#7], and transgenic expression of human IL-37 attenuates inflammation-driven sleep responses elicited by IL-1\\u03b2 or LPS [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established how the IL-37 precursor is converted to a mature cytokine, identifying caspase-1 as the principal processing enzyme and defining the maturation step that governs its activity.\",\n      \"evidence\": \"In vitro caspase cleavage assays against multiple caspases plus adenoviral expression in HEK293 cells\",\n      \"pmids\": [\"12096920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological trigger and cellular context of caspase-1 processing not defined\", \"Whether mature form is the dominant secreted species in vivo not established\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined IL-37's receptor selectivity, showing it engages IL-18R\\u03b1 with affinity weaker than IL-18 and does not bind IL-1R or ST2R, framing it as an IL-18R\\u03b1-directed ligand without agonist output.\",\n      \"evidence\": \"Binding screen with soluble receptor-Fc fusions and IFN-\\u03b3 induction assay in KG1a cells\",\n      \"pmids\": [\"12096920\", \"12381835\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinity for IL-18R\\u03b1 is low, leaving physiological relevance of this binding open\", \"No downstream signaling readout established for IL-37 binding\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed that caspase-1 processing dramatically increases homodimerization affinity, linking maturation to a defined biophysical state of the cytokine.\",\n      \"evidence\": \"Association constant measurement comparing pro- and mature forms\",\n      \"pmids\": [\"12096920\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of homodimerization not resolved\", \"Single-lab biophysical measurement without orthogonal structural confirmation\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Explained why IL-37 lacks IL-18 agonist activity by demonstrating its failure to recruit IL-18R\\u03b2 into the ternary signaling complex.\",\n      \"evidence\": \"Chemical cross-linking and SDS-PAGE analysis of receptor complex formation\",\n      \"pmids\": [\"12381835\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IL-18R\\u03b1 engagement actively antagonizes IL-18 signaling not shown\", \"Structural basis of failed co-receptor recruitment not resolved experimentally\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified a second anti-inflammatory mechanism in which IL-37 complexes with IL-18BP to cooperatively enhance IL-18 neutralization.\",\n      \"evidence\": \"Chemical cross-linking plus IFN-\\u03b3 inhibition assays in an NK cell line and PBMCs\",\n      \"pmids\": [\"12381835\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enhancement is modest (~25-30%) and concentration-dependent\", \"Stoichiometry and architecture of the IL-37/IL-18BP complex not determined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Placed IL-37 in an in vivo anti-tumor pathway, showing its effect requires IL-12, IFN-\\u03b3, Fas-ligand, and intact adaptive immunity.\",\n      \"evidence\": \"Genetic epistasis across IL-12-/-, IFN-\\u03b3-/-, FasL-/-, NKT-deficient, nude, and SCID mice with intratumoral adenoviral gene transfer\",\n      \"pmids\": [\"12496389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between IL-37 expression and IL-12/IFN-\\u03b3/FasL induction not defined\", \"Reliance on adenoviral overexpression rather than endogenous IL-37\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Raised the possibility of a receptor-independent intranuclear role for IL-37 by reporting nuclear localization analogous to IL-1\\u03b1 and IL-33.\",\n      \"evidence\": \"Nuclear localization described in a review citing prior experimental work\",\n      \"pmids\": [\"22047735\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Reported in review without primary method detail\", \"No nuclear transcriptional target or partner identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated an in vivo anti-inflammatory function by showing IL-37 attenuates inflammation-driven sleep responses triggered by IL-1\\u03b2 or LPS.\",\n      \"evidence\": \"Sleep recording in human IL-37b transgenic versus wild-type mice with LPS, IL-1\\u03b2, and influenza challenge\",\n      \"pmids\": [\"28070566\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway connecting IL-37 to dampened NREMS responses not mapped\", \"Relies on human transgene in mouse background\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proposed a structural rationale for IL-37's failure to recruit IL-18R\\u03b2, implicating the N-terminal loop and an N297 glycan steric block, and a distinct IL-37/IL-18BP binding mode.\",\n      \"evidence\": \"Homology modeling, AlphaFold2 multimer prediction, and molecular dynamics simulations (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.09.21.613817\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational prediction with no experimental validation\", \"Predicted N-terminal loop and glycan roles not tested by mutagenesis\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The signaling output of IL-37 engagement of IL-18R\\u03b1 and the molecular basis of its proposed intranuclear transcriptional role remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No intracellular signaling effector identified for IL-37 receptor binding\", \"No nuclear binding partner or target gene established\", \"Endogenous (non-overexpression) anti-inflammatory mechanism not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IL18R1\", \"IL18BP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}