{"gene":"IL36G","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2004,"finding":"IL-36γ (IL-1F9), along with IL-1F6 and IL-1F8, signals through IL-1Rrp2 (IL-1R6) as the primary receptor and IL-1RAcP as a co-receptor to activate the NF-κB pathway and MAPKs (JNK and ERK1/2). Antibodies against IL-1Rrp2 or IL-1RAcP, and transfection of cytoplasmically deleted IL-1RAcP, each blocked NF-κB activation, establishing both receptor components as required for signaling.","method":"NF-κB reporter assays, antibody blocking, dominant-negative IL-1RAcP transfection, MAPK activation assays in Jurkat cells and NCI/ADR-RES cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (reporter assay, antibody neutralization, dominant-negative transfection) in multiple cell lines; foundational paper with 346 citations","pmids":["14734551"],"is_preprint":false},{"year":2003,"finding":"IL-1Rrp2 mRNA is constitutively expressed in mouse brain astrocytes and microglia but not in neurons, identifying glia as potential cellular targets of IL-36γ. However, IL-1F9 (IL-36γ) failed to activate NF-κB, MAPKs, or induce IL-6 release in glial cultures, or elicit fever/anorexia in vivo, suggesting it may trigger alternative pathways distinct from classical IL-1β signaling in this context.","method":"RT-PCR for IL-1Rrp2 expression, NF-κB activation assays, MAPK activation assays, IL-6 ELISA, in vivo intracerebroventricular injection in rats","journal":"Journal of neuroimmunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays in primary cells and in vivo, but findings are largely negative for IL-36γ activity; single lab","pmids":["12799018"],"is_preprint":false},{"year":2010,"finding":"IL-36γ (IL-1F9) protein is secreted from primary human bronchial epithelial cells following TLR3 stimulation (dsRNA), and acts on lung fibroblasts (which express IL-1Rrp2) to activate MAPKs and NF-κB and induce expression of neutrophil chemokines IL-8 and CXCL3 and the Th17 chemokine CCL20.","method":"ELISA for IL-1F9 secretion, RT-PCR for receptor expression on fibroblasts, MAPK and NF-κB activation assays, chemokine ELISA in primary human lung fibroblasts","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal assays (protein secretion, receptor expression, signaling, downstream gene induction) in primary human cells; 122 citations","pmids":["20870894"],"is_preprint":false},{"year":2012,"finding":"IL-36γ expression in myeloid cells (predendritic KG1 cells and murine DC) is directly regulated by the transcription factor T-bet (Tbx21). Promoter analysis identified a functional T-bet binding site and a κB site required for efficient IL-36γ induction. Mature IL-36γ in turn induces an inflammatory gene expression profile in primary human keratinocytes, including upregulation of TNFα, CCL20, S100A7, inducible NOS, and IL-36γ itself.","method":"siRNA knockdown of T-bet combined with genome-wide mRNA expression analysis, promoter analysis, T-bet knockout mice, ectopic T-bet expression in HaCaT keratinocytes, IL-36γ treatment of primary keratinocytes with mRNA profiling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — genome-wide screen validated by KO animals and ectopic expression; promoter analysis identifies mechanism; multiple orthogonal approaches","pmids":["23095752"],"is_preprint":false},{"year":2012,"finding":"IL-1Rrp2 (IL-1R6) expression is unique to dendritic cells (DCs) within the human myelomonocytic lineage. IL-36γ (IL-1F9) signaling through IL-1Rrp2 on monocyte-derived DCs induces DC maturation, evidenced by increased HLA-DR and CD83 expression and decreased CD1a, and stimulates downstream inflammatory responses.","method":"Flow cytometry for IL-1Rrp2 expression across myelomonocytic subsets, IL-1F9 stimulation of MDDCs with measurement of surface maturation markers (HLA-DR, CD83, CD1a, CD40, CD80) and cytokine secretion (IL-18, IL-12p70), lymphocyte proliferation assay","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — functional assays in primary human cells with multiple readouts; single lab","pmids":["22144259"],"is_preprint":false},{"year":2022,"finding":"PCSK9 negatively regulates IL-36γ expression in keratinocytes. siRNA knockdown of PCSK9 in cultured keratinocytes increased IL-36G expression, and human skin homozygous for a PCSK9 loss-of-function SNP (rs662145 C>T) showed lower PCSK9 and higher IL-36G expression, establishing an inverse regulatory relationship.","method":"PCSK9 siRNA knockdown in keratinocytes with RT-PCR/RNA-Seq for IL36G, single-cell RNA-Seq, IHC, genotyping of skin samples for PCSK9 SNP","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA knockdown confirmed by SNP genotype experiment; two orthogonal approaches; single lab","pmids":["35862195"],"is_preprint":false},{"year":2022,"finding":"IL-36γ induces ERK1/2 activation and promotes colony formation, migration, and invasion in human gastric cancer cell lines (AGS, MKN1, MKN45). These pro-neoplastic effects are inhibited by the natural antagonist IL-36 receptor antagonist (IL-36RA), indicating they are receptor-mediated.","method":"ERK1/2 phosphorylation assay (Western blot), colony formation assay, migration and invasion assays, IL-36RA inhibition experiments in human gastric cancer cell lines","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional readouts with receptor antagonist control; single lab","pmids":["35512531"],"is_preprint":false},{"year":2024,"finding":"A distinct subset of neutrophil-like monocytes (cachexia-inducible monocytes, CiMs) expressing IL-36γ emerges in advanced cancer and drives skeletal muscle wasting. Toll-like receptor 4 (TLR4) signaling induces CiMs. Genetic inhibition of IL-36γ-mediated signaling attenuates skeletal muscle loss and rescues cachexia phenotypes in advanced cancer mouse models.","method":"Transcriptome analysis of monocyte subsets, in vivo genetic inhibition of IL36G signaling in cancer models with measurement of muscle mass and cachexia phenotypes, TLR4 stimulation experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic loss-of-function with defined phenotypic rescue; unbiased transcriptomic identification plus mechanistic follow-up; single lab but rigorous","pmids":["39266531"],"is_preprint":false},{"year":2024,"finding":"Active vitamin D3 (1,25VD3) suppresses IL-36γ production in human nasal epithelial cells (HNECs) and polyp tissue explants. Impaired local conversion of 25VD3 to 1,25VD3 (due to reduced CYP27B1 expression) in chronic rhinosinusitis with nasal polyps results in elevated IL-36γ and neutrophilic inflammation. siRNA knockdown of CYP27B1 abolished the suppressive effect of 25VD3 on IL-36γ production.","method":"siRNA knockdown of CYP27B1 in HNECs, 1,25VD3 and 25VD3 treatment with IL-36γ ELISA, RNA sequencing for VD3-regulated genes, polyp tissue explant experiments","journal":"Rhinology","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA knockdown with functional readout plus ex vivo tissue experiments; single lab","pmids":["38085113"],"is_preprint":false},{"year":2026,"finding":"IL-36γ promotes pyroptosis and NLRP3 inflammasome activation in macrophages via NF-κB signaling. IL-36G overexpression activated NF-κB and enhanced NLRP3 inflammasome activation; these effects were blocked by the NF-κB inhibitor BAY 11-7085. IL-36G knockout mice subjected to cecal ligation and puncture showed improved survival, reduced lung injury, and suppressed NF-κB-mediated NLRP3 activation.","method":"IL-36G overexpression and knockdown in RAW264.7 macrophages with Western blot for NF-κB and NLRP3 pathway proteins, flow cytometry for pyroptosis, NF-κB inhibitor (BAY 11-7085) treatment, IL-36G knockout mice in CLP sepsis model with lung injury and cytokine readouts","journal":"Experimental lung research","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro gain/loss-of-function plus in vivo KO with defined mechanistic pathway; single lab, newly published","pmids":["41889065"],"is_preprint":false},{"year":2019,"finding":"Scratch injury of confluent human keratinocytes selectively and significantly upregulates IL36G mRNA and intracellular protein, but IL-36γ protein is not secreted extracellularly under these conditions, establishing that intracellular IL-36γ accumulation is a response to mechanical injury in keratinocytes.","method":"qRT-PCR, ELISA, Western blotting of scratched normal human keratinocyte monolayers","journal":"Journal of dermatological science","confidence":"Medium","confidence_rationale":"Tier 3 — multiple assay types (mRNA, intracellular protein, secretion) but mechanistic follow-up limited; single lab","pmids":["31010609"],"is_preprint":false}],"current_model":"IL-36γ (IL-36G/IL-1F9) is a secreted and intracellular IL-1 family cytokine that signals through a heterodimeric receptor complex of IL-1Rrp2 (IL-1R6) and IL-1RAcP to activate NF-κB and MAPKs (JNK, ERK1/2) in epithelial cells, fibroblasts, and immune cells; its expression is transcriptionally induced by T-bet and NF-κB in myeloid cells and repressed by vitamin D3/VDR signaling in epithelial cells, while PCSK9 inversely regulates its expression in keratinocytes; downstream it drives neutrophilic chemokine production, DC maturation, macrophage pyroptosis via NLRP3/NF-κB, and skeletal muscle wasting in cancer cachexia through a TLR4-induced neutrophil-like monocyte subset."},"narrative":{"teleology":[{"year":2003,"claim":"Testing whether IL-36γ activates classical IL-1-type neuroinflammatory signaling revealed that, despite receptor expression on glia, IL-36γ fails to activate NF-κB, MAPKs, or induce IL-6 in brain glial cells or elicit sickness behaviors in vivo, establishing that its signaling is cell-type restricted.","evidence":"NF-κB and MAPK assays in primary astrocytes/microglia, IL-6 ELISA, intracerebroventricular injection in rats","pmids":["12799018"],"confidence":"Medium","gaps":["Findings are entirely negative; alternative signaling pathways in glia not tested","No positive-control cell type included for comparison"]},{"year":2004,"claim":"Defining the receptor and signaling requirements for IL-36γ established that it signals through IL-1Rrp2 (IL-1R6) as its primary receptor and IL-1RAcP as an obligate co-receptor to activate NF-κB and MAPKs (JNK, ERK1/2), placing it firmly within the IL-1 signaling paradigm.","evidence":"NF-κB reporter assays, antibody blocking of IL-1Rrp2 and IL-1RAcP, dominant-negative IL-1RAcP transfection, MAPK phosphorylation in Jurkat and NCI/ADR-RES cells","pmids":["14734551"],"confidence":"High","gaps":["Structural basis of IL-36γ–IL-1Rrp2 interaction not resolved","Signaling events downstream of MAPKs not characterized"]},{"year":2010,"claim":"Demonstrating that TLR3-stimulated bronchial epithelial cells secrete IL-36γ, which then acts on lung fibroblasts to induce neutrophil chemokines (IL-8, CXCL3) and CCL20, established the epithelium-to-mesenchyme paracrine circuit through which IL-36γ promotes neutrophilic airway inflammation.","evidence":"IL-1F9 ELISA on epithelial supernatants, RT-PCR for IL-1Rrp2 on fibroblasts, chemokine induction assays in primary human lung fibroblasts","pmids":["20870894"],"confidence":"High","gaps":["In vivo contribution to airway neutrophilia not demonstrated","Processing protease responsible for generating active IL-36γ in this context unknown"]},{"year":2012,"claim":"Identifying T-bet and NF-κB as direct transcriptional regulators of IL-36γ in myeloid cells, and showing that mature IL-36γ induces an inflammatory gene program (TNFα, CCL20, S100A7, iNOS, and IL-36γ itself) in keratinocytes, revealed a feed-forward amplification loop linking innate immune activation to epithelial inflammation.","evidence":"T-bet siRNA knockdown, T-bet KO mice, ectopic T-bet expression, promoter analysis identifying T-bet and κB sites, IL-36γ stimulation of primary keratinocytes with mRNA profiling","pmids":["23095752"],"confidence":"High","gaps":["Relative contributions of T-bet versus NF-κB to IL-36γ transcription in disease states not quantified","Feed-forward loop not tested in vivo"]},{"year":2012,"claim":"Showing that IL-1Rrp2 expression within the myelomonocytic lineage is restricted to dendritic cells and that IL-36γ induces DC maturation markers (HLA-DR, CD83) defined DCs as key immune effectors of IL-36γ signaling.","evidence":"Flow cytometry for IL-1Rrp2 across myelomonocytic subsets, IL-36γ stimulation of monocyte-derived DCs with surface marker and cytokine readouts","pmids":["22144259"],"confidence":"Medium","gaps":["Whether IL-36γ-matured DCs skew specific T-helper responses not resolved","Single lab; receptor restriction not confirmed in tissue-resident DC subsets"]},{"year":2019,"claim":"Demonstrating that mechanical injury selectively upregulates intracellular IL-36γ protein in keratinocytes without extracellular secretion established that IL-36γ can function as a damage-associated intracellular signal in skin.","evidence":"qRT-PCR, ELISA, Western blot of scratch-wounded human keratinocyte monolayers","pmids":["31010609"],"confidence":"Medium","gaps":["No intracellular binding partners or signaling role identified","Mechanism of non-conventional secretion or release upon cell death not tested"]},{"year":2022,"claim":"Identifying PCSK9 as a negative regulator of IL-36γ expression in keratinocytes — validated by both siRNA knockdown and a human loss-of-function PCSK9 SNP — linked lipid metabolism regulators to IL-36γ-driven skin inflammation.","evidence":"PCSK9 siRNA in keratinocytes with RT-PCR/RNA-Seq, scRNA-Seq, IHC, genotyping of PCSK9 rs662145 in human skin","pmids":["35862195"],"confidence":"Medium","gaps":["Mechanism by which PCSK9 represses IL36G transcription unknown","Whether PCSK9-mediated regulation operates outside the skin not tested"]},{"year":2022,"claim":"Demonstrating that IL-36γ activates ERK1/2 and promotes colony formation, migration, and invasion of gastric cancer cells — effects blocked by IL-36RA — extended IL-36γ's functional repertoire to receptor-dependent pro-neoplastic signaling.","evidence":"ERK1/2 Western blot, colony formation, migration/invasion assays with IL-36RA inhibition in AGS, MKN1, MKN45 gastric cancer lines","pmids":["35512531"],"confidence":"Medium","gaps":["In vivo tumor-promoting role not tested","Downstream transcriptional program mediating pro-neoplastic effects unknown"]},{"year":2024,"claim":"Discovering that a TLR4-induced neutrophil-like monocyte subset (CiMs) expressing IL-36γ drives skeletal muscle wasting in cancer cachexia — with genetic inhibition of IL-36γ rescuing muscle loss in vivo — established IL-36γ as a causal effector of cancer-associated cachexia.","evidence":"Transcriptomics of monocyte subsets, in vivo genetic inhibition of IL-36γ signaling in advanced cancer mouse models with muscle mass measurements","pmids":["39266531"],"confidence":"High","gaps":["Direct target cells and receptor on muscle not identified","Whether IL-36γ acts directly on myocytes or through intermediary signals not resolved"]},{"year":2024,"claim":"Showing that active vitamin D3 suppresses IL-36γ production in nasal epithelial cells and that impaired local vitamin D conversion (reduced CYP27B1) elevates IL-36γ in nasal polyps established a VDR-dependent suppressive circuit that, when disrupted, promotes neutrophilic upper airway inflammation.","evidence":"CYP27B1 siRNA in HNECs, 1,25VD3 treatment with IL-36γ ELISA, RNA-Seq, nasal polyp tissue explants","pmids":["38085113"],"confidence":"Medium","gaps":["Whether VDR directly binds the IL36G promoter not shown","Relevance to other mucosal sites not tested"]},{"year":2026,"claim":"Demonstrating that IL-36γ drives macrophage pyroptosis through NF-κB-dependent NLRP3 inflammasome activation — confirmed by NF-κB inhibitor blockade and improved survival in IL-36G knockout sepsis models — established IL-36γ as a proximal trigger of inflammasome-mediated cell death in sepsis-related lung injury.","evidence":"IL-36G overexpression/knockdown in RAW264.7, NF-κB inhibitor BAY 11-7085, IL-36G KO mice in cecal ligation and puncture model with lung injury and survival readouts","pmids":["41889065"],"confidence":"Medium","gaps":["Single lab, newly published, awaits independent confirmation","Whether IL-36γ directly primes or activates NLRP3 versus acting through transcriptional upregulation not fully dissected"]},{"year":null,"claim":"Key unresolved questions include the identity of the protease(s) that generate active IL-36γ in vivo in different tissues, the structural basis of IL-36γ–IL-1Rrp2–IL-1RAcP complex assembly, and whether IL-36γ has intracellular signaling functions independent of its cell-surface receptor.","evidence":"","pmids":[],"confidence":"Low","gaps":["Activating protease identity remains unknown for most tissue contexts","No crystal structure of the ternary signaling complex","Intracellular accumulation without secretion (keratinocyte injury) has no known functional consequence"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,2,4,6,7,9]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,3,4,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,6]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9]}],"complexes":[],"partners":["IL1RL2","IL1RAP","IL36RN"],"other_free_text":[]},"mechanistic_narrative":"IL-36γ (IL-1F9) is a pro-inflammatory IL-1 family cytokine that signals through the IL-1Rrp2 (IL-1R6)/IL-1RAcP heterodimeric receptor complex to activate NF-κB and MAPKs (JNK, ERK1/2), thereby driving neutrophil chemokine production, dendritic cell maturation, macrophage pyroptosis via NLRP3 inflammasome engagement, and cancer-associated skeletal muscle wasting [PMID:14734551, PMID:20870894, PMID:22144259, PMID:41889065, PMID:39266531]. Its transcription in myeloid cells is directly controlled by T-bet and NF-κB, while epithelial expression is suppressed by active vitamin D3 through VDR signaling and inversely regulated by PCSK9 in keratinocytes [PMID:23095752, PMID:38085113, PMID:35862195]. IL-36γ is released from bronchial epithelial cells upon TLR3 stimulation and accumulates intracellularly in keratinocytes after mechanical injury, and it acts in a paracrine fashion on fibroblasts and dendritic cells to amplify inflammatory cascades including IL-8, CXCL3, and CCL20 induction [PMID:20870894, PMID:31010609, PMID:23095752]. In advanced cancer, a TLR4-induced neutrophil-like monocyte subset expressing IL-36γ drives cachexia, and genetic inhibition of IL-36γ signaling rescues muscle wasting in vivo [PMID:39266531]."},"prefetch_data":{"uniprot":{"accession":"Q9NZH8","full_name":"Interleukin-36 gamma","aliases":["IL-1-related protein 2","IL-1RP2","Interleukin-1 epsilon","IL-1 epsilon","Interleukin-1 family member 9","IL-1F9","Interleukin-1 homolog 1","IL-1H1"],"length_aa":169,"mass_kda":18.7,"function":"Cytokine that binds to and signals through the IL1RL2/IL-36R receptor which in turn activates NF-kappa-B and MAPK signaling pathways in target cells. Part of the IL-36 signaling system that is thought to be present in epithelial barriers and to take part in local inflammatory response; similar to the IL-1 system with which it shares the coreceptor IL1RAP. Seems to be involved in skin inflammatory response by acting on keratinocytes, dendritic cells and indirectly on T-cells to drive tissue infiltration, cell maturation and cell proliferation. In cultured keratinocytes induces the expression of macrophage, T-cell, and neutrophil chemokines, such as CCL3, CCL4, CCL5, CCL2, CCL17, CCL22, CL20, CCL5, CCL2, CCL17, CCL22, CXCL8, CCL20 and CXCL1; also stimulates its own expression and that of the prototypic cutaneous pro-inflammatory parameters TNF, S100A7/psoriasin and inducible NOS. May play a role in pro-inflammatory responses during particular neutrophilic airway inflammation: activates mitogen-activated protein kinases and NF-kappa B in primary lung fibroblasts, and stimulates the expression of IL-8 and CXCL3 and Th17 chemokine CCL20 in lung fibroblasts. May be involved in the innate immune response to fungal pathogens, such as Aspergillus fumigatus","subcellular_location":"Cytoplasm; Secreted","url":"https://www.uniprot.org/uniprotkb/Q9NZH8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL36G","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL36G","total_profiled":1310},"omim":[{"mim_id":"615296","title":"INTERLEUKIN 1 FAMILY, MEMBER 10; IL1F10","url":"https://www.omim.org/entry/615296"},{"mim_id":"607211","title":"CASPASE RECRUITMENT DOMAIN-CONTAINING PROTEIN 14; CARD14","url":"https://www.omim.org/entry/607211"},{"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":"605507","title":"INTERLEUKIN 36 RECEPTOR ANTAGONIST; IL36RN","url":"https://www.omim.org/entry/605507"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"cervix","ntpm":10.8},{"tissue":"esophagus","ntpm":13.3},{"tissue":"lymphoid tissue","ntpm":36.9},{"tissue":"skin 1","ntpm":28.0}],"url":"https://www.proteinatlas.org/search/IL36G"},"hgnc":{"alias_symbol":["IL-1H1","IL-1RP2","IL-1F9","IL1H1","IL1E"],"prev_symbol":["IL1F9"]},"alphafold":{"accession":"Q9NZH8","domains":[{"cath_id":"2.80.10.50","chopping":"24-168","consensus_level":"high","plddt":96.0659,"start":24,"end":168}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZH8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZH8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZH8-F1-predicted_aligned_error_v6.png","plddt_mean":90.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL36G","jax_strain_url":"https://www.jax.org/strain/search?query=IL36G"},"sequence":{"accession":"Q9NZH8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NZH8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NZH8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZH8"}},"corpus_meta":[{"pmid":"14734551","id":"PMC_14734551","title":"Interleukin (IL)-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP to activate the pathway leading to NF-kappaB and MAPKs.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14734551","citation_count":346,"is_preprint":false},{"pmid":"25525775","id":"PMC_25525775","title":"IL-36γ (IL-1F9) is a biomarker for psoriasis skin lesions.","date":"2014","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/25525775","citation_count":204,"is_preprint":false},{"pmid":"20870894","id":"PMC_20870894","title":"Regulation and function of the IL-1 family cytokine IL-1F9 in human bronchial epithelial cells.","date":"2010","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20870894","citation_count":122,"is_preprint":false},{"pmid":"22144259","id":"PMC_22144259","title":"Expression of IL-1Rrp2 by human myelomonocytic cells is unique to DCs and facilitates DC maturation by IL-1F8 and IL-1F9.","date":"2012","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22144259","citation_count":83,"is_preprint":false},{"pmid":"23095752","id":"PMC_23095752","title":"IL-36γ/IL-1F9, an innate T-bet target in myeloid cells.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23095752","citation_count":54,"is_preprint":false},{"pmid":"31010609","id":"PMC_31010609","title":"Cyto/chemokine profile of in vitro scratched keratinocyte model: Implications of significant upregulation of CCL20, CXCL8 and IL36G in Koebner phenomenon.","date":"2019","source":"Journal of dermatological science","url":"https://pubmed.ncbi.nlm.nih.gov/31010609","citation_count":43,"is_preprint":false},{"pmid":"12799018","id":"PMC_12799018","title":"IL-1Rrp2 expression and IL-1F9 (IL-1H1) actions in brain cells.","date":"2003","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/12799018","citation_count":35,"is_preprint":false},{"pmid":"35862195","id":"PMC_35862195","title":"Proprotein convertase subtilisin/kexin type 9 is a psoriasis-susceptibility locus that is negatively related to IL36G.","date":"2022","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/35862195","citation_count":29,"is_preprint":false},{"pmid":"30634937","id":"PMC_30634937","title":"Polymorphisms in IL36G gene are associated with plaque psoriasis.","date":"2019","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30634937","citation_count":21,"is_preprint":false},{"pmid":"35512531","id":"PMC_35512531","title":"IL-36G promotes cancer-cell intrinsic hallmarks in human gastric cancer cells.","date":"2022","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/35512531","citation_count":12,"is_preprint":false},{"pmid":"38085113","id":"PMC_38085113","title":"Impaired local Vitamin D3 metabolism contributes to IL-36g overproduction in epithelial cells in chronic rhinosinusitis with nasal polyps.","date":"2024","source":"Rhinology","url":"https://pubmed.ncbi.nlm.nih.gov/38085113","citation_count":12,"is_preprint":false},{"pmid":"39266531","id":"PMC_39266531","title":"IL36G-producing neutrophil-like monocytes promote cachexia in cancer.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39266531","citation_count":10,"is_preprint":false},{"pmid":"39757204","id":"PMC_39757204","title":"Quantum molecular resonance ameliorates atopic dermatitis through suppression of IL36G and SPRR2B.","date":"2025","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/39757204","citation_count":1,"is_preprint":false},{"pmid":"40159643","id":"PMC_40159643","title":"Monocytes Expressing IL-36G Play a Crucial Role in Atopic Dermatitis.","date":"2025","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40159643","citation_count":0,"is_preprint":false},{"pmid":"36325341","id":"PMC_36325341","title":"Corrigendum: IL36G is associated with cutaneous antiviral competence in psoriasis.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36325341","citation_count":0,"is_preprint":false},{"pmid":"41889065","id":"PMC_41889065","title":"IL-36G drives sepsis-induced lung injury via NF-κB-dependent activation of the NLRP3 inflammasome in macrophage pyroptosis.","date":"2026","source":"Experimental lung research","url":"https://pubmed.ncbi.nlm.nih.gov/41889065","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.29.25326433","title":"Single-cell immune profiling at time of  <i>M. tuberculosis</i>  exposure reveals antigen-reactive programs that predict progression to active disease","date":"2025-04-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.29.25326433","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10431,"output_tokens":3286,"usd":0.040292},"stage2":{"model":"claude-opus-4-6","input_tokens":6761,"output_tokens":3220,"usd":0.171458},"total_usd":0.21175,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-36γ (IL-1F9), along with IL-1F6 and IL-1F8, signals through IL-1Rrp2 (IL-1R6) as the primary receptor and IL-1RAcP as a co-receptor to activate the NF-κB pathway and MAPKs (JNK and ERK1/2). Antibodies against IL-1Rrp2 or IL-1RAcP, and transfection of cytoplasmically deleted IL-1RAcP, each blocked NF-κB activation, establishing both receptor components as required for signaling.\",\n      \"method\": \"NF-κB reporter assays, antibody blocking, dominant-negative IL-1RAcP transfection, MAPK activation assays in Jurkat cells and NCI/ADR-RES cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (reporter assay, antibody neutralization, dominant-negative transfection) in multiple cell lines; foundational paper with 346 citations\",\n      \"pmids\": [\"14734551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IL-1Rrp2 mRNA is constitutively expressed in mouse brain astrocytes and microglia but not in neurons, identifying glia as potential cellular targets of IL-36γ. However, IL-1F9 (IL-36γ) failed to activate NF-κB, MAPKs, or induce IL-6 release in glial cultures, or elicit fever/anorexia in vivo, suggesting it may trigger alternative pathways distinct from classical IL-1β signaling in this context.\",\n      \"method\": \"RT-PCR for IL-1Rrp2 expression, NF-κB activation assays, MAPK activation assays, IL-6 ELISA, in vivo intracerebroventricular injection in rats\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays in primary cells and in vivo, but findings are largely negative for IL-36γ activity; single lab\",\n      \"pmids\": [\"12799018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-36γ (IL-1F9) protein is secreted from primary human bronchial epithelial cells following TLR3 stimulation (dsRNA), and acts on lung fibroblasts (which express IL-1Rrp2) to activate MAPKs and NF-κB and induce expression of neutrophil chemokines IL-8 and CXCL3 and the Th17 chemokine CCL20.\",\n      \"method\": \"ELISA for IL-1F9 secretion, RT-PCR for receptor expression on fibroblasts, MAPK and NF-κB activation assays, chemokine ELISA in primary human lung fibroblasts\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays (protein secretion, receptor expression, signaling, downstream gene induction) in primary human cells; 122 citations\",\n      \"pmids\": [\"20870894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IL-36γ expression in myeloid cells (predendritic KG1 cells and murine DC) is directly regulated by the transcription factor T-bet (Tbx21). Promoter analysis identified a functional T-bet binding site and a κB site required for efficient IL-36γ induction. Mature IL-36γ in turn induces an inflammatory gene expression profile in primary human keratinocytes, including upregulation of TNFα, CCL20, S100A7, inducible NOS, and IL-36γ itself.\",\n      \"method\": \"siRNA knockdown of T-bet combined with genome-wide mRNA expression analysis, promoter analysis, T-bet knockout mice, ectopic T-bet expression in HaCaT keratinocytes, IL-36γ treatment of primary keratinocytes with mRNA profiling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide screen validated by KO animals and ectopic expression; promoter analysis identifies mechanism; multiple orthogonal approaches\",\n      \"pmids\": [\"23095752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IL-1Rrp2 (IL-1R6) expression is unique to dendritic cells (DCs) within the human myelomonocytic lineage. IL-36γ (IL-1F9) signaling through IL-1Rrp2 on monocyte-derived DCs induces DC maturation, evidenced by increased HLA-DR and CD83 expression and decreased CD1a, and stimulates downstream inflammatory responses.\",\n      \"method\": \"Flow cytometry for IL-1Rrp2 expression across myelomonocytic subsets, IL-1F9 stimulation of MDDCs with measurement of surface maturation markers (HLA-DR, CD83, CD1a, CD40, CD80) and cytokine secretion (IL-18, IL-12p70), lymphocyte proliferation assay\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assays in primary human cells with multiple readouts; single lab\",\n      \"pmids\": [\"22144259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PCSK9 negatively regulates IL-36γ expression in keratinocytes. siRNA knockdown of PCSK9 in cultured keratinocytes increased IL-36G expression, and human skin homozygous for a PCSK9 loss-of-function SNP (rs662145 C>T) showed lower PCSK9 and higher IL-36G expression, establishing an inverse regulatory relationship.\",\n      \"method\": \"PCSK9 siRNA knockdown in keratinocytes with RT-PCR/RNA-Seq for IL36G, single-cell RNA-Seq, IHC, genotyping of skin samples for PCSK9 SNP\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA knockdown confirmed by SNP genotype experiment; two orthogonal approaches; single lab\",\n      \"pmids\": [\"35862195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-36γ induces ERK1/2 activation and promotes colony formation, migration, and invasion in human gastric cancer cell lines (AGS, MKN1, MKN45). These pro-neoplastic effects are inhibited by the natural antagonist IL-36 receptor antagonist (IL-36RA), indicating they are receptor-mediated.\",\n      \"method\": \"ERK1/2 phosphorylation assay (Western blot), colony formation assay, migration and invasion assays, IL-36RA inhibition experiments in human gastric cancer cell lines\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional readouts with receptor antagonist control; single lab\",\n      \"pmids\": [\"35512531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A distinct subset of neutrophil-like monocytes (cachexia-inducible monocytes, CiMs) expressing IL-36γ emerges in advanced cancer and drives skeletal muscle wasting. Toll-like receptor 4 (TLR4) signaling induces CiMs. Genetic inhibition of IL-36γ-mediated signaling attenuates skeletal muscle loss and rescues cachexia phenotypes in advanced cancer mouse models.\",\n      \"method\": \"Transcriptome analysis of monocyte subsets, in vivo genetic inhibition of IL36G signaling in cancer models with measurement of muscle mass and cachexia phenotypes, TLR4 stimulation experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic loss-of-function with defined phenotypic rescue; unbiased transcriptomic identification plus mechanistic follow-up; single lab but rigorous\",\n      \"pmids\": [\"39266531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Active vitamin D3 (1,25VD3) suppresses IL-36γ production in human nasal epithelial cells (HNECs) and polyp tissue explants. Impaired local conversion of 25VD3 to 1,25VD3 (due to reduced CYP27B1 expression) in chronic rhinosinusitis with nasal polyps results in elevated IL-36γ and neutrophilic inflammation. siRNA knockdown of CYP27B1 abolished the suppressive effect of 25VD3 on IL-36γ production.\",\n      \"method\": \"siRNA knockdown of CYP27B1 in HNECs, 1,25VD3 and 25VD3 treatment with IL-36γ ELISA, RNA sequencing for VD3-regulated genes, polyp tissue explant experiments\",\n      \"journal\": \"Rhinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA knockdown with functional readout plus ex vivo tissue experiments; single lab\",\n      \"pmids\": [\"38085113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"IL-36γ promotes pyroptosis and NLRP3 inflammasome activation in macrophages via NF-κB signaling. IL-36G overexpression activated NF-κB and enhanced NLRP3 inflammasome activation; these effects were blocked by the NF-κB inhibitor BAY 11-7085. IL-36G knockout mice subjected to cecal ligation and puncture showed improved survival, reduced lung injury, and suppressed NF-κB-mediated NLRP3 activation.\",\n      \"method\": \"IL-36G overexpression and knockdown in RAW264.7 macrophages with Western blot for NF-κB and NLRP3 pathway proteins, flow cytometry for pyroptosis, NF-κB inhibitor (BAY 11-7085) treatment, IL-36G knockout mice in CLP sepsis model with lung injury and cytokine readouts\",\n      \"journal\": \"Experimental lung research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro gain/loss-of-function plus in vivo KO with defined mechanistic pathway; single lab, newly published\",\n      \"pmids\": [\"41889065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Scratch injury of confluent human keratinocytes selectively and significantly upregulates IL36G mRNA and intracellular protein, but IL-36γ protein is not secreted extracellularly under these conditions, establishing that intracellular IL-36γ accumulation is a response to mechanical injury in keratinocytes.\",\n      \"method\": \"qRT-PCR, ELISA, Western blotting of scratched normal human keratinocyte monolayers\",\n      \"journal\": \"Journal of dermatological science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — multiple assay types (mRNA, intracellular protein, secretion) but mechanistic follow-up limited; single lab\",\n      \"pmids\": [\"31010609\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-36γ (IL-36G/IL-1F9) is a secreted and intracellular IL-1 family cytokine that signals through a heterodimeric receptor complex of IL-1Rrp2 (IL-1R6) and IL-1RAcP to activate NF-κB and MAPKs (JNK, ERK1/2) in epithelial cells, fibroblasts, and immune cells; its expression is transcriptionally induced by T-bet and NF-κB in myeloid cells and repressed by vitamin D3/VDR signaling in epithelial cells, while PCSK9 inversely regulates its expression in keratinocytes; downstream it drives neutrophilic chemokine production, DC maturation, macrophage pyroptosis via NLRP3/NF-κB, and skeletal muscle wasting in cancer cachexia through a TLR4-induced neutrophil-like monocyte subset.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL-36γ (IL-1F9) is a pro-inflammatory IL-1 family cytokine that signals through the IL-1Rrp2 (IL-1R6)/IL-1RAcP heterodimeric receptor complex to activate NF-κB and MAPKs (JNK, ERK1/2), thereby driving neutrophil chemokine production, dendritic cell maturation, macrophage pyroptosis via NLRP3 inflammasome engagement, and cancer-associated skeletal muscle wasting [PMID:14734551, PMID:20870894, PMID:22144259, PMID:41889065, PMID:39266531]. Its transcription in myeloid cells is directly controlled by T-bet and NF-κB, while epithelial expression is suppressed by active vitamin D3 through VDR signaling and inversely regulated by PCSK9 in keratinocytes [PMID:23095752, PMID:38085113, PMID:35862195]. IL-36γ is released from bronchial epithelial cells upon TLR3 stimulation and accumulates intracellularly in keratinocytes after mechanical injury, and it acts in a paracrine fashion on fibroblasts and dendritic cells to amplify inflammatory cascades including IL-8, CXCL3, and CCL20 induction [PMID:20870894, PMID:31010609, PMID:23095752]. In advanced cancer, a TLR4-induced neutrophil-like monocyte subset expressing IL-36γ drives cachexia, and genetic inhibition of IL-36γ signaling rescues muscle wasting in vivo [PMID:39266531].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Testing whether IL-36γ activates classical IL-1-type neuroinflammatory signaling revealed that, despite receptor expression on glia, IL-36γ fails to activate NF-κB, MAPKs, or induce IL-6 in brain glial cells or elicit sickness behaviors in vivo, establishing that its signaling is cell-type restricted.\",\n      \"evidence\": \"NF-κB and MAPK assays in primary astrocytes/microglia, IL-6 ELISA, intracerebroventricular injection in rats\",\n      \"pmids\": [\"12799018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Findings are entirely negative; alternative signaling pathways in glia not tested\", \"No positive-control cell type included for comparison\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defining the receptor and signaling requirements for IL-36γ established that it signals through IL-1Rrp2 (IL-1R6) as its primary receptor and IL-1RAcP as an obligate co-receptor to activate NF-κB and MAPKs (JNK, ERK1/2), placing it firmly within the IL-1 signaling paradigm.\",\n      \"evidence\": \"NF-κB reporter assays, antibody blocking of IL-1Rrp2 and IL-1RAcP, dominant-negative IL-1RAcP transfection, MAPK phosphorylation in Jurkat and NCI/ADR-RES cells\",\n      \"pmids\": [\"14734551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of IL-36γ–IL-1Rrp2 interaction not resolved\", \"Signaling events downstream of MAPKs not characterized\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that TLR3-stimulated bronchial epithelial cells secrete IL-36γ, which then acts on lung fibroblasts to induce neutrophil chemokines (IL-8, CXCL3) and CCL20, established the epithelium-to-mesenchyme paracrine circuit through which IL-36γ promotes neutrophilic airway inflammation.\",\n      \"evidence\": \"IL-1F9 ELISA on epithelial supernatants, RT-PCR for IL-1Rrp2 on fibroblasts, chemokine induction assays in primary human lung fibroblasts\",\n      \"pmids\": [\"20870894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution to airway neutrophilia not demonstrated\", \"Processing protease responsible for generating active IL-36γ in this context unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying T-bet and NF-κB as direct transcriptional regulators of IL-36γ in myeloid cells, and showing that mature IL-36γ induces an inflammatory gene program (TNFα, CCL20, S100A7, iNOS, and IL-36γ itself) in keratinocytes, revealed a feed-forward amplification loop linking innate immune activation to epithelial inflammation.\",\n      \"evidence\": \"T-bet siRNA knockdown, T-bet KO mice, ectopic T-bet expression, promoter analysis identifying T-bet and κB sites, IL-36γ stimulation of primary keratinocytes with mRNA profiling\",\n      \"pmids\": [\"23095752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of T-bet versus NF-κB to IL-36γ transcription in disease states not quantified\", \"Feed-forward loop not tested in vivo\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showing that IL-1Rrp2 expression within the myelomonocytic lineage is restricted to dendritic cells and that IL-36γ induces DC maturation markers (HLA-DR, CD83) defined DCs as key immune effectors of IL-36γ signaling.\",\n      \"evidence\": \"Flow cytometry for IL-1Rrp2 across myelomonocytic subsets, IL-36γ stimulation of monocyte-derived DCs with surface marker and cytokine readouts\",\n      \"pmids\": [\"22144259\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IL-36γ-matured DCs skew specific T-helper responses not resolved\", \"Single lab; receptor restriction not confirmed in tissue-resident DC subsets\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that mechanical injury selectively upregulates intracellular IL-36γ protein in keratinocytes without extracellular secretion established that IL-36γ can function as a damage-associated intracellular signal in skin.\",\n      \"evidence\": \"qRT-PCR, ELISA, Western blot of scratch-wounded human keratinocyte monolayers\",\n      \"pmids\": [\"31010609\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No intracellular binding partners or signaling role identified\", \"Mechanism of non-conventional secretion or release upon cell death not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying PCSK9 as a negative regulator of IL-36γ expression in keratinocytes — validated by both siRNA knockdown and a human loss-of-function PCSK9 SNP — linked lipid metabolism regulators to IL-36γ-driven skin inflammation.\",\n      \"evidence\": \"PCSK9 siRNA in keratinocytes with RT-PCR/RNA-Seq, scRNA-Seq, IHC, genotyping of PCSK9 rs662145 in human skin\",\n      \"pmids\": [\"35862195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PCSK9 represses IL36G transcription unknown\", \"Whether PCSK9-mediated regulation operates outside the skin not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that IL-36γ activates ERK1/2 and promotes colony formation, migration, and invasion of gastric cancer cells — effects blocked by IL-36RA — extended IL-36γ's functional repertoire to receptor-dependent pro-neoplastic signaling.\",\n      \"evidence\": \"ERK1/2 Western blot, colony formation, migration/invasion assays with IL-36RA inhibition in AGS, MKN1, MKN45 gastric cancer lines\",\n      \"pmids\": [\"35512531\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo tumor-promoting role not tested\", \"Downstream transcriptional program mediating pro-neoplastic effects unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovering that a TLR4-induced neutrophil-like monocyte subset (CiMs) expressing IL-36γ drives skeletal muscle wasting in cancer cachexia — with genetic inhibition of IL-36γ rescuing muscle loss in vivo — established IL-36γ as a causal effector of cancer-associated cachexia.\",\n      \"evidence\": \"Transcriptomics of monocyte subsets, in vivo genetic inhibition of IL-36γ signaling in advanced cancer mouse models with muscle mass measurements\",\n      \"pmids\": [\"39266531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target cells and receptor on muscle not identified\", \"Whether IL-36γ acts directly on myocytes or through intermediary signals not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing that active vitamin D3 suppresses IL-36γ production in nasal epithelial cells and that impaired local vitamin D conversion (reduced CYP27B1) elevates IL-36γ in nasal polyps established a VDR-dependent suppressive circuit that, when disrupted, promotes neutrophilic upper airway inflammation.\",\n      \"evidence\": \"CYP27B1 siRNA in HNECs, 1,25VD3 treatment with IL-36γ ELISA, RNA-Seq, nasal polyp tissue explants\",\n      \"pmids\": [\"38085113\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether VDR directly binds the IL36G promoter not shown\", \"Relevance to other mucosal sites not tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrating that IL-36γ drives macrophage pyroptosis through NF-κB-dependent NLRP3 inflammasome activation — confirmed by NF-κB inhibitor blockade and improved survival in IL-36G knockout sepsis models — established IL-36γ as a proximal trigger of inflammasome-mediated cell death in sepsis-related lung injury.\",\n      \"evidence\": \"IL-36G overexpression/knockdown in RAW264.7, NF-κB inhibitor BAY 11-7085, IL-36G KO mice in cecal ligation and puncture model with lung injury and survival readouts\",\n      \"pmids\": [\"41889065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, newly published, awaits independent confirmation\", \"Whether IL-36γ directly primes or activates NLRP3 versus acting through transcriptional upregulation not fully dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the protease(s) that generate active IL-36γ in vivo in different tissues, the structural basis of IL-36γ–IL-1Rrp2–IL-1RAcP complex assembly, and whether IL-36γ has intracellular signaling functions independent of its cell-surface receptor.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Activating protease identity remains unknown for most tissue contexts\", \"No crystal structure of the ternary signaling complex\", \"Intracellular accumulation without secretion (keratinocyte injury) has no known functional consequence\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 2, 4, 6, 7, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 3, 4, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IL1RL2\",\n      \"IL1RAP\",\n      \"IL36RN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}