{"gene":"IL18","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1995,"finding":"IL-18 (originally called IGIF) was cloned as a novel cytokine that induces IFN-γ production by T cells and enhances NK cell cytotoxicity; the gene encodes a 192-amino acid precursor protein with a mature form of 157 amino acids, with no homology to other known cytokines at the time.","method":"cDNA cloning, recombinant protein expression, IFN-γ induction assay in spleen cells, NK cytotoxicity assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — original cloning paper with functional validation, foundational discovery replicated extensively","pmids":["7477296"],"is_preprint":false},{"year":1996,"finding":"Human IL-18 cDNA was cloned; recombinant human IL-18 induced IFN-γ production in mitogen-stimulated PBMC, enhanced NK cell cytotoxicity, augmented GM-CSF production, and decreased IL-10 production, establishing it as a pleiotropic cytokine designated IL-18.","method":"cDNA cloning from human liver library, recombinant protein expression in E. coli, PBMC stimulation assays, ELISA","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — recombinant protein with multiple functional assays, foundational characterization paper","pmids":["8666798"],"is_preprint":false},{"year":1996,"finding":"IL-18 (IGIF) synergizes with IL-12 to induce IFN-γ production from human T cells; IL-18 promotes T cell proliferation through an IL-2-dependent pathway and enhances Th1 cytokine production (IFN-γ, IL-2, GM-CSF) without affecting IL-4 or IL-10, demonstrating a distinct pathway from IL-12.","method":"Anti-CD3 stimulation of human T cells, ELISA, CTLL-2 bioassay, neutralizing antibodies","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, foundational synergy paper replicated across many subsequent studies","pmids":["8766574"],"is_preprint":false},{"year":1997,"finding":"Caspase-1 (ICE) cleaves the pro-IL-18 precursor at the authentic processing site with high efficiency, generating the active mature form; caspase-1-deficient Kupffer cells synthesized pro-IL-18 but failed to process it, and caspase-1-deficient mice showed diminished serum IFN-γ and IL-18 after LPS challenge.","method":"In vitro cleavage assay with recombinant ICE, ICE-knockout mice, LPS/P. acnes challenge model, ELISA","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution plus knockout mouse validation, widely replicated","pmids":["8999548"],"is_preprint":false},{"year":1997,"finding":"The human IL-18 receptor (IL-18Rα) was purified and identified as IL-1Rrp (IL-1 receptor-related protein); IL-18 binding to L428 cells had a Kd of ~18.5 nM with ~18,000 sites/cell; IL-18 binding was not competed by IL-1β; expression of IL-1Rrp cDNA in COS-1 cells conferred both IL-18 binding and signal transduction capacity.","method":"Radioligand binding assay, receptor purification by lectin and mAb chromatography, COS-1 cell expression system, N-terminal peptide sequencing","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — receptor purification, binding kinetics, and functional reconstitution in heterologous cells","pmids":["9325300"],"is_preprint":false},{"year":1997,"finding":"IL-18 together with IL-12 induces IFN-γ production from activated B cells, which in turn inhibits IL-4-dependent IgE and IgG1 production and enhances IgG2a production; B cells from normal mice can become IFN-γ-producing cells in IFN-γ-deficient host mice in response to IL-12 plus IL-18.","method":"In vitro anti-CD40/IL-4 stimulation, ELISA, in vivo mouse models (N. brasiliensis, anti-IgD), adoptive transfer into IFN-γ KO mice","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — multiple in vitro and in vivo methods demonstrating B cell IFN-γ production downstream of IL-18+IL-12","pmids":["9108085"],"is_preprint":false},{"year":1999,"finding":"IL-18 can act as a potent co-inducer of IL-13 in NK and T cells when combined with IL-2 (independent of IFN-γ), demonstrating that IL-18 can promote Th2-type cytokine production in addition to its Th1-inducing activities, depending on the cytokine milieu.","method":"NK and T cell stimulation assays, ELISA, Northern blot, IFN-γ knockout mouse cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple cell types and IFN-γ KO controls establishing IFN-γ-independent IL-13 induction","pmids":["10227975"],"is_preprint":false},{"year":1999,"finding":"Bioactive (mature) IL-18 is predominantly present in Crohn's disease mucosa as an 18-kDa form, whereas in controls it exists as the 24-kDa precursor; active caspase-1 (ICE) p20 subunit is expressed in IBD samples, and antisense knockdown of IL-18 in CD LPMC reduced IFN-γ expression, placing IL-18 upstream of IFN-γ production in CD.","method":"Western blot, RT-PCR, antisense oligonucleotide knockdown, IFN-γ ELISA","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods but in a disease context without reconstitution; causal link established by antisense knockdown","pmids":["10384110"],"is_preprint":false},{"year":2000,"finding":"IL-18 signals through a receptor system (IL-18Rα and IL-18Rβ) analogous to the IL-1 receptor, activating the same downstream signal transduction pathway including NF-κB; IL-18-deficient mice have impaired NK cell activity and in vivo Th1 responses.","method":"IL-18 knockout mice, NK cytotoxicity assays, cytokine measurements","journal":"Current opinion in immunology","confidence":"High","confidence_rationale":"Tier 2 — knockout mouse studies replicated across multiple labs establishing IL-18R signaling pathway","pmids":["10679398"],"is_preprint":false},{"year":2000,"finding":"IL-18 activates NF-κB and AP-1 in CD4+ T cells (Jurkat cells), driving IL-2 gene transcription and protein production; depletion of IL-18 from sarcoid epithelial lining fluid with neutralizing antibodies abrogated AP-1/NF-κB activation and IL-2 production, positioning IL-18 upstream of T cell IL-2 production.","method":"Transcription factor EMSA, luciferase/reporter assays, neutralizing antibody depletion, ELISA, Jurkat cell stimulation","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods in cell-based system; neutralizing antibody depletion provides functional validation","pmids":["11035116"],"is_preprint":false},{"year":2001,"finding":"Human peripheral blood neutrophils constitutively express IL-18Rα and IL-18Rβ; IL-18 induces cytokine/chemokine release (protein synthesis-dependent), up-regulates CD11b, induces granule release, and enhances the respiratory burst after fMLP, but does not affect neutrophil apoptosis; IL-18 administration promoted neutrophil accumulation in vivo and IL-18 neutralization suppressed carrageenan-induced footpad inflammation.","method":"Flow cytometry, ELISA, myeloperoxidase assay, in vivo mouse models, neutralizing antibodies","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple in vitro functional assays plus in vivo neutralization confirming neutrophil-activating role","pmids":["11509635"],"is_preprint":false},{"year":2002,"finding":"IL-18 expression in human atherosclerotic plaque occurs predominantly as the mature 18-kDa form in macrophages; endothelial cells, smooth muscle cells, and macrophages all constitutively express functional IL-18Rα/β complex; IL-18 signaling in these vascular cells induces IL-6, IL-8, ICAM-1, and MMP-1/-9/-13 expression, and IL-18 plus IL-12 induces IFN-γ in smooth muscle cells (but not endothelial cells).","method":"Immunohistochemistry, Western blot, in vitro cell stimulation, ELISA, RT-PCR","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple cell types, orthogonal methods, functional receptor signaling validated in primary and cultured vascular cells","pmids":["11805151"],"is_preprint":false},{"year":2002,"finding":"IL-18 regulates IL-1β-dependent hepatic melanoma metastasis: B16 melanoma-conditioned medium stimulates hepatic sinusoidal endothelial cells to sequentially release TNF-α, IL-1β, and IL-18; exogenous IL-18 increases VCAM-1 expression on HSE and melanoma cell adhesion via a VCAM-1-dependent (not IL-1R or TNF-dependent) mechanism; anti-IL-18 or IL-18BP abolished this adhesion.","method":"In vitro co-culture adhesion assays, intrasplenic tumor injection model, IL-1β and caspase-1 KO mice, neutralizing antibodies, VCAM-1 blocking","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — genetic knockouts plus neutralizing antibodies plus in vivo model with multiple orthogonal readouts","pmids":["10639148"],"is_preprint":false},{"year":2002,"finding":"ATP release from monocytes stimulated with microbial ligands or uric acid triggers autocrine P2X7 receptor activation, leading to K+ efflux and phospholipase A2 activation, which are required for caspase-1-dependent maturation and secretion of both IL-1β and IL-18; P2X7 antagonists or apyrase prevent IL-18 secretion.","method":"Primary human monocyte cultures, ATP measurement, P2X7 antagonists, apyrase treatment, caspase-1 inhibitors, ELISA, intracellular flow cytometry","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — multiple pharmacological interventions and a gain-of-function mutant inflammasome control establishing the ATP-P2X7-IL-18 secretion pathway","pmids":["18523012"],"is_preprint":false},{"year":2003,"finding":"IL-18 activates neutrophils via TNF-α induction, which drives production of leukotriene B4 (LTB4), causing neutrophil accumulation; IL-18-induced neutrophil recruitment and LTB4 production were blocked by LTB4 synthesis inhibitor MK-886, LTB4 receptor antagonist CP-105696, anti-TNF-α antibody, and was absent in TNFRp55-/- mice.","method":"In vivo peritoneal neutrophil recruitment model, LTB4 ELISA, pharmacological inhibitors, TNFRp55 knockout mice, anti-TNF-α neutralization","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacological epistasis establishing the IL-18→TNF-α→LTB4→neutrophil axis","pmids":["12847274"],"is_preprint":false},{"year":2003,"finding":"Bcl6 functions as a sequence-specific transcriptional repressor of the IL-18 gene; a Bcl6-binding DNA sequence (IL-18BS) was identified upstream of exon 1 of the murine IL-18 gene and in the human IL-18 promoter; Bcl6 binding to IL-18BS was detected by gel retardation and ChIP assays and diminished after LPS stimulation; Bcl6 repressed IL-18 promoter-driven luciferase expression in an IL-18BS-dependent manner.","method":"Gel retardation (EMSA), chromatin immunoprecipitation (ChIP), luciferase reporter assay, dominant-negative transfection, Bcl6 KO macrophages, RT-PCR","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple direct biochemical methods (ChIP, EMSA, reporter assay) in both KO and dominant-negative contexts","pmids":["12817026"],"is_preprint":false},{"year":2003,"finding":"Langerhans cell-derived IL-18 contributes to contact hypersensitivity initiation; mature IL-18 (requiring caspase-1 cleavage) is necessary for IL-12-stimulated IFN-γ production by lymph node cells; caspase-1-/- LN cells showed impaired IFN-γ production that was restored by exogenous IL-18; CHS was significantly inhibited by neutralizing anti-IL-18 antibody and in caspase-1-/- mice.","method":"Murine CHS model, IL-18 neutralizing antibodies, caspase-1 KO mice, in vitro IFN-γ production assays, exogenous IL-18 rescue","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout and antibody neutralization with clear rescue experiment linking caspase-1 processing to functional IL-18","pmids":["11907086"],"is_preprint":false},{"year":2004,"finding":"A highly stable human IL-18 protein was generated by replacing cysteines with serines based on the 3D crystal structure and receptor-binding mechanism, retaining full biological activity, establishing that the cysteine residues are not required for function but contribute to multimerization-based inactivation.","method":"Site-directed mutagenesis, recombinant protein production, biological activity assay (IFN-γ induction), structural analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 — structure-guided mutagenesis with functional validation in single study","pmids":["15047165"],"is_preprint":false},{"year":2004,"finding":"IL-18 directly induces maturation of myeloid dendritic cells (but not differentiation of monocytes): IL-18 stimulation increased CD83, HLA-DR, and co-stimulatory molecules on monocyte-derived DCs and KG-1 cells, decreased pinocytosis, and enhanced alloreactive T cell stimulatory capacity.","method":"Flow cytometry, pinocytosis assay, mixed lymphocyte reaction, monocyte-derived DC culture","journal":"Cellular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional readouts of DC maturation in human primary cells and cell line","pmids":["15135292"],"is_preprint":false},{"year":2005,"finding":"NK cells trigger immature DCs to polarize secretory lysosomes containing IL-18 toward the NK cell contact site in a Ca2+-dependent, tubulin-mediated manner; IL-18 is released at the synaptic cleft (not diffusely), activating only the interacting NK cell; this establishes a polarized secretion mechanism for the leaderless cytokine IL-18.","method":"Confocal microscopy, lysosome tracking, Ca2+ chelation, tubulin disruption, ELISA of synaptic vs. non-synaptic fractions","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 — direct live imaging of polarized secretion with pharmacological dissection of the Ca2+/tubulin mechanism","pmids":["15802534"],"is_preprint":false},{"year":2007,"finding":"IL-18 enhances IFN-γ-induced production of CXCL9, CXCL10, and CXCL11 in human keratinocytes by activating NF-κB, STAT1, and IRF-1 through PI3K/Akt and MEK/ERK pathways; antisense oligonucleotides against NF-κB p50/p65 or STAT1 suppressed chemokine production; IL-18 induced phosphorylation of ERK and Akt.","method":"Antisense oligonucleotides, ELISA, RT-PCR, kinase inhibitors (LY294002, SB203580, PD98059), Western blot for phospho-ERK and phospho-Akt, primary human keratinocyte cultures","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple pathway inhibitors and antisense knockdowns with consistent results defining the signaling cascade","pmids":["17274000"],"is_preprint":false},{"year":2007,"finding":"CD8+ T cell-derived granzyme B cleaves pro-IL-18 in keratinocytes to generate mature IL-18, functioning as an alternative IL-18 converting enzyme; GrB+ /caspase-1- CD8 T cells co-cultured with IFN-γ-treated HaCaT keratinocytes transferred GrB into HaCaT cells and increased mature IL-18 in culture supernatant.","method":"CD8+ T cell and HaCaT keratinocyte co-culture, ELISA for mature IL-18, flow cytometry for GrB, PCR for caspase-1 expression","journal":"Archives of dermatological research","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional assay showing GrB-mediated IL-18 processing; prior reconstitution data with recombinant proteins referenced","pmids":["23820889"],"is_preprint":false},{"year":2009,"finding":"IL-18 downregulates collagen production in human dermal fibroblasts via ERK phosphorylation and Ets-1 transcription factor; siRNA-mediated Ets-1 knockdown blocked IL-18-regulated collagen expression; ERK inhibitor PD98059 blocked IL-18's inhibitory effect; IL-18 also inhibited TGF-β-induced collagen expression and reduced collagen in SSc fibroblasts.","method":"siRNA knockdown (Ets-1), ERK inhibitor (PD98059), Western blot (phospho-ERK), RT-PCR, ELISA, primary human dermal fibroblast cultures","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 1-2 — siRNA knockdown and pharmacological inhibition with mechanistic pathway placement","pmids":["19865096"],"is_preprint":false},{"year":2009,"finding":"IL-18 induces osteopontin (OPN) expression in cardiac fibroblasts via IRF-1 transcriptional regulation; blockade of IL-18 receptor with neutralizing antibody abolished OPN expression; IRF1 mutation or siRNA reduced IL-18 and OPN expression; IRF1-mutant mice showed reduced IL-18/OPN expression and less cardiac fibrosis with pressure overload.","method":"Cardiac fibroblast culture, IL-18R neutralizing antibody, IRF1 siRNA/mutation, mouse pressure overload model, echocardiography, Western blot, RT-PCR","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 2 — receptor blockade, siRNA, and in vivo genetic approach converge on the IL-18→IRF-1→OPN→fibrosis pathway","pmids":["19429811"],"is_preprint":false},{"year":2012,"finding":"TRAM (TICAM-2) acts as a sorting adaptor for MyD88 in IL-18 signaling; a direct interaction between MyD88-TIR domain and TRAM was demonstrated in vitro; TRAM-deficient mice and RNAi experiments showed reduced IL-18 signal transduction; live cell imaging showed co-localized accumulation of MyD88 and TRAM at membrane regions; TRAM binding sites on MyD88 overlap with those for Mal/TIRAP.","method":"In vitro protein interaction assay, RNAi knockdown, TRAM-deficient mice, live cell imaging (co-localization), cell-based IL-18 signaling assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — direct binding assay, KO mice, RNAi, and live imaging all supporting TRAM as IL-18 signaling adaptor","pmids":["22685567"],"is_preprint":false},{"year":2013,"finding":"Inflammasomes activate caspase-1, which processes pro-IL-18 (and pro-IL-1β) to their mature active forms; NLRP3 and other NLR inflammasomes serve as the upstream activating platforms for caspase-1-dependent IL-18 maturation.","method":"Inflammasome reconstitution, caspase-1 activity assays, IL-18 maturation assays, NLR overexpression/knockout systems","journal":"Nature reviews. Immunology","confidence":"High","confidence_rationale":"Tier 1 — extensive reconstitution and genetic evidence across many studies, highly cited review summarizing mechanistic data","pmids":["23702978"],"is_preprint":false},{"year":2014,"finding":"The crystal structure of IL-18 bound to the ectodomain of IL-18Rα was determined; surface charge complementarity determines ligand-binding specificity of primary receptors in the IL-1 receptor family; the IL-18 signaling complex adopts an architecture similar to other agonistic IL-1 family cytokines.","method":"X-ray crystallography, structural analysis, binding site mapping","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 — crystal structure providing direct structural mechanism for IL-18/IL-18Rα recognition","pmids":["25261253"],"is_preprint":false},{"year":2015,"finding":"The NLRP1 inflammasome is the specific inflammasome that activates IL-18 to prevent obesity and metabolic syndrome; NLRP1-deficient mice phenocopy IL-18-deficient mice with spontaneous obesity; mice with activating NLRP1 mutations have elevated IL-18, decreased adiposity, and are resistant to diet-induced metabolic dysfunction; HFD-induced fatal cachexia in NLRP1-activating mutant mice was prevented by IL-18 genetic deletion.","method":"NLRP1 and IL-18 knockout mice, NLRP1 activating-mutation knock-in mice, IL-18 ELISA, body composition analysis, high-fat/high-protein diet challenges, genetic rescue (IL-18 deletion)","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 — epistasis established by multiple genetic models including activating mutation rescue and IL-18 deletion reversal","pmids":["26603191"],"is_preprint":false},{"year":2015,"finding":"IL-18 inhibits goblet cell maturation in intestinal epithelial cells by regulating the transcriptional program instructing goblet cell development; deletion of IL-18 or IL-18R1 in intestinal epithelial cells conferred protection from colitis; deletion of IL-18BP caused severe colitis with goblet cell loss that was rescued in IL-18BP-/-;IL-18rΔ/EC double mice, demonstrating the effect is mediated at the level of epithelial IL-18 signaling.","method":"Conditional epithelial cell-specific IL-18R1 and IL-18BP knockout mice, RNA-seq transcriptional analysis, histology, genetic epistasis (double knockout rescue)","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — clean genetic epistasis with conditional knockouts and double-KO rescue, published in Cell","pmids":["26638073"],"is_preprint":false},{"year":2015,"finding":"NK cells require IL-18 signaling (via MyD88, but not IL-1R) for robust primary expansion during MCMV infection but not for memory cell maintenance or recall responses; IL-12/STAT4 signaling in activated NK cells upregulates MyD88 expression, which then mediates IL-18 downstream signaling.","method":"MCMV infection model, IL-18R-/-, MyD88-/-, IL-1R-/- mice, STAT4-/- mice, adoptive transfer, flow cytometry","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic knockouts establishing stage-specific requirement and signaling pathway","pmids":["25589075"],"is_preprint":false},{"year":2016,"finding":"IL-18 promotes neonatal sepsis lethality via IL-1R1 signaling (not adaptive immunity); IL-18 increases IL-17A production by intestinal γδT cells and Ly6G+ myeloid cells; blocking IL-17A reduced IL-18-potentiated mortality, defining an IL-18→IL-1R1→IL-17A lethal axis in neonatal sepsis.","method":"IL-18-null neonatal mice, IL-1R1 KO mice, IL-18 replenishment, anti-IL-17A blockade, genome-wide mRNA analysis of human neonatal sepsis samples, flow cytometry","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — genetic and antibody epistasis establishing the mechanistic pathway with both mouse and human data","pmids":["27114524"],"is_preprint":false},{"year":2018,"finding":"Inflammasome-dependent activation of IL-18 (but not IL-1β) within the myocardium upon β1-AR/ROS signaling is the critical upstream regulator for chemokine expression, macrophage infiltration, and cardiac fibrosis; genetic deletion of IL-18 or NLRP3 attenuated chemokine expression and macrophage infiltration; IL-18 neutralizing antibodies selectively blocked chemokines and proinflammatory cytokines but not growth factors.","method":"Isoproterenol-induced β-AR stimulation model, IL-18 KO and NLRP3 KO mice, cytokine array, IL-18 neutralizing antibodies, cardiac histology","journal":"European heart journal","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic and antibody approaches converging on IL-18 as specific upstream regulator in the NLRP3→IL-18→chemokine→macrophage cardiac inflammation pathway","pmids":["28549109"],"is_preprint":false},{"year":2020,"finding":"IL-18BP is upregulated in diverse human and mouse tumors and limits IL-18 anti-tumor activity; 'decoy-resistant' IL-18 (DR-18) engineered by directed evolution is impervious to IL-18BP inhibition while maintaining signaling; DR-18 promoted poly-functional CD8+ T cells, reduced TOX+ exhausted CD8+ T cells, expanded TCF1+ stem-like CD8+ T cells, and enhanced NK cell maturation.","method":"Directed protein evolution, tumor mouse models, flow cytometry (CD8+ T cell subset analysis), IL-18BP neutralization, anti-PD-1 resistant tumor models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — engineered protein with defined mechanism plus multiple in vivo tumor models establishing IL-18BP as the key barrier to IL-18 signaling","pmids":["32581358"],"is_preprint":false},{"year":2020,"finding":"Enteric neurons are the essential non-redundant source of IL-18 required for homeostatic antimicrobial protein (AMP) production by goblet cells; deletion of IL-18 specifically from enteric neurons (not immune or epithelial cells) rendered mice susceptible to invasive Salmonella infection; enteric neuronal IL-18 is specifically required for goblet cell AMP production as established by RNA-seq and single-cell sequencing.","method":"Cell type-specific conditional IL-18 knockout mice (neurons vs. immune vs. epithelial), Salmonella infection model, confocal microscopy, smFISH, RNA-seq, single-cell RNA-seq","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — cell-type specific conditional knockouts with multiple transcriptomic readouts; published in Cell","pmids":["31923399"],"is_preprint":false},{"year":2021,"finding":"GSDMD activation in intestinal epithelial cells (but not immune cells) promotes IL-18 release (without affecting IL-18 transcript or maturation levels) to mediate goblet cell loss and colitis development; commensal E. coli overgrowth during colitis mediates GSDMD activation; Gsdmd-deficient mice had reduced colitis severity.","method":"DSS colitis model, Gsdmd KO mice, cell-type specific reconstitution, IL-18 ELISA (protein vs. transcript), 16S microbiome analysis, E. coli colonization experiments","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic and microbiome manipulations establishing the microbiota→GSDMD→IL-18 release→goblet cell loss pathway","pmids":["34721422"],"is_preprint":false},{"year":2021,"finding":"GSDMD pore structure establishes electrostatic filtering of cargo release: the GSDMD pore conduit is predominantly negatively charged, while IL-18 precursor has an acidic domain removed by caspase-1 cleavage; mature (positively charged) IL-18 passes through GSDMD pores faster than negatively charged precursor; mutation of GSDMD acidic residues compromised this selectivity.","method":"Cryo-EM structure of GSDMD pore and prepore, liposome permeabilization assay, mutagenesis, macrophage IL-18 secretion assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure plus mutagenesis plus functional liposome assay establishing electrostatic mechanism of IL-18 release through GSDMD","pmids":["33883744"],"is_preprint":false},{"year":2023,"finding":"Human caspase-4 (but not mouse caspase-11) directly and efficiently processes pro-IL-18 at the same tetrapeptide site as caspase-1; the crystal structure of the caspase-4/pro-IL-18 complex reveals a binary substrate-recognition mechanism: the catalytic pocket engages the tetrapeptide, and a unique exosite (also used by caspase-1 and -5) recognizes a structure formed jointly by the propeptide and post-cleavage-site sequences; caspase-11 cannot target pro-IL-18 due to a structural deviation at the exosite; pro-IL-18 has autoinhibitory interactions between the propeptide and post-cleavage-site region; caspase cleavage induces conformational changes generating two critical IL-18Rα receptor-binding sites.","method":"Crystal structure (caspase-4/pro-IL-18 complex), in vitro cleavage assay, bacterial infection models, exosite mutagenesis (caspase-11 to restore IL-18 processing), IL-18Rα binding assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus in vitro reconstitution plus mutagenesis plus bacterial infection model in a single study","pmids":["37993714"],"is_preprint":false},{"year":2024,"finding":"The GFPT2-O-GlcNAcylation-YBX1 axis promotes IL-18 secretion in pancreatic cancer cells: GFPT2-mediated O-GlcNAcylation causes YBX1 nuclear translocation, where YBX1 functions as a transcription factor to promote IL-18 transcription; confirmed by Co-IP and protein mass spectrometry identifying O-GlcNAcylated YBX1.","method":"Co-IP, protein mass spectrometry, cellular proteomics, transcription factor ChIP/reporter, YBX1 knockdown/overexpression","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP/MS and functional transcription assays in single study without independent replication","pmids":["38575607"],"is_preprint":false},{"year":2024,"finding":"PTBP3 promotes IL-18 exon skipping to generate a tumor-specific isoform ΔIL-18; H3K36me3 couples IL-18 transcription and alternative splicing by recruiting PTBP3 via MRG15; SETD2 (H3K36 methyltransferase) binds hnRNPL to interfere with PTBP3 binding to IL-18 pre-mRNA; ΔIL-18 promotes immune escape by reducing FBXO38-mediated PD-1 ubiquitin degradation in CD8+ T cells.","method":"mRNA-seq/GEO analysis, multi-omics, luciferase reporter for splicing, antisense oligonucleotides, HuPBMC mouse model, SETD2/PTBP3/MRG15 interaction assays, PD-1 ubiquitination assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — multiple molecular assays in single study; novel mechanistic finding but requires independent replication","pmids":["39116343"],"is_preprint":false},{"year":2025,"finding":"Caspase-3 cleavage of IL-18 in cancer cells generates a 15-kDa 'short IL-18' form that is distinct from mature IL-18: short IL-18 is not secreted and does not bind IL-18Rα; instead it translocates to the nucleus, facilitating STAT1 Ser727 phosphorylation via CDK8, and enhancing ISG15 expression and secretion; this cascade mobilizes NK cells with increased cytotoxicity to eliminate syngeneic tumors.","method":"Caspase-3 cleavage assay, subcellular fractionation, IL-18Rα binding assay, nuclear translocation imaging, CDK8 inhibition, ISG15 ELISA, syngeneic tumor models, NK cell depletion, colorectal cancer patient tissue analysis","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1-2 — novel cleavage product characterized by multiple orthogonal biochemical methods plus in vivo tumor models with mechanistic pathway (STAT1 Ser727-CDK8-ISG15-NK activation)","pmids":["39891018"],"is_preprint":false}],"current_model":"IL-18 is synthesized as an inactive 24-kDa precursor constitutively present in most cells; it is processed to its active 18-kDa mature form primarily by caspase-1 within NLRP1/NLRP3/NLRC4 inflammasome complexes (and also by caspase-4/5 in a noncanonical pathway, granzyme B, and other proteases), after which GSDMD pores mediate its electrostatic-selective release; mature IL-18 signals through a heterodimeric receptor (IL-18Rα/IL-18Rβ) via MyD88 (recruited by the sorting adaptor TRAM) to activate NF-κB, AP-1, and MAPK pathways, driving IFN-γ production synergistically with IL-12 in NK and T cells, activating neutrophils, promoting DC maturation, and regulating intestinal epithelial goblet cell homeostasis; its bioactivity is tightly controlled by the high-affinity decoy receptor IL-18BP; additionally, caspase-3 generates a distinct nuclear 15-kDa short IL-18 that activates a CDK8-STAT1-ISG15-NK cell anti-tumor pathway independently of IL-18Rα."},"narrative":{"teleology":[{"year":1995,"claim":"The identification of IL-18 (IGIF) as a novel cytokine that induces IFN-γ and enhances NK cytotoxicity established its foundational role as a Th1-promoting factor distinct from IL-12.","evidence":"cDNA cloning from murine liver with recombinant protein validation in spleen cell IFN-γ induction and NK cytotoxicity assays","pmids":["7477296"],"confidence":"High","gaps":["No receptor or signaling pathway identified","Processing mechanism from precursor unknown","Cellular sources not defined beyond liver"]},{"year":1997,"claim":"Demonstration that caspase-1 is the principal pro-IL-18 converting enzyme and that IL-18Rα (IL-1Rrp) is the cognate receptor resolved how IL-18 is activated and how it initiates signaling.","evidence":"In vitro caspase-1 cleavage assays, caspase-1 KO mice with diminished serum IL-18/IFN-γ; receptor purification from L428 cells with radioligand binding and COS-1 reconstitution","pmids":["8999548","9325300"],"confidence":"High","gaps":["Co-receptor (IL-18Rβ) not yet characterized","Inflammasome platform identity unknown","Mechanism of leaderless secretion unresolved"]},{"year":1999,"claim":"IL-18 was shown to act beyond Th1 polarization, co-inducing IL-13 with IL-2 in NK/T cells independently of IFN-γ, and its caspase-1-processed mature form was linked to Crohn's disease mucosal inflammation, broadening its functional scope.","evidence":"NK/T cell stimulation with IFN-γ KO controls for IL-13 induction; Western blot and antisense knockdown in Crohn's disease lamina propria mononuclear cells","pmids":["10227975","10384110"],"confidence":"High","gaps":["Epithelial cell-intrinsic effects of IL-18 in IBD not dissected","Precise Th2 vs. Th1 polarizing conditions incompletely defined"]},{"year":2000,"claim":"Elucidation of the IL-18Rα/IL-18Rβ heterodimer signaling through NF-κB and AP-1 via MyD88 established IL-18's signal transduction architecture and its capacity to drive IL-2 production in T cells.","evidence":"IL-18 KO mice, Jurkat cell EMSA/reporter assays, neutralizing antibody depletion of IL-18 from sarcoid fluid","pmids":["10679398","11035116"],"confidence":"High","gaps":["Role of sorting adaptors (e.g., TRAM) in MyD88 recruitment unknown","Downstream transcription factor hierarchy for different cell types unresolved"]},{"year":2001,"claim":"IL-18 was shown to directly activate neutrophils and subsequently to drive neutrophil recruitment via a TNF-α→LTB4 axis, extending its function beyond lymphocyte biology to innate granulocyte responses.","evidence":"Neutrophil stimulation assays, in vivo IL-18 neutralization in carrageenan inflammation, TNFRp55 KO mice and LTB4 inhibitors","pmids":["11509635","12847274"],"confidence":"High","gaps":["Whether IL-18 directly activates other granulocyte types not established","Neutrophil IL-18 autocrine loops not explored"]},{"year":2005,"claim":"Discovery of polarized IL-18 secretion from dendritic cell lysosomes toward NK cells at the immunological synapse revealed a directed, non-classical release mechanism for this leaderless cytokine.","evidence":"Confocal imaging of DC–NK synapses, Ca2+ chelation and tubulin disruption, synaptic vs. non-synaptic fraction ELISA","pmids":["15802534"],"confidence":"High","gaps":["Molecular identity of the lysosomal IL-18 loading machinery unknown","Relationship to later-discovered GSDMD pore-mediated release not addressed"]},{"year":2007,"claim":"Mapping of IL-18-activated PI3K/Akt and MEK/ERK pathways converging on NF-κB, STAT1, and IRF-1 to drive chemokine expression in keratinocytes, and the identification of granzyme B as an alternative pro-IL-18 convertase, expanded the signaling and processing repertoire.","evidence":"Kinase inhibitor panel and antisense knockdown in primary keratinocytes; CD8+ T cell/HaCaT co-culture showing GrB-dependent mature IL-18 generation","pmids":["17274000","23820889"],"confidence":"High","gaps":["Relative contribution of GrB vs. caspase-1 in vivo not quantified","Cell-type specificity of PI3K/Akt vs. MAPK engagement not fully explored"]},{"year":2012,"claim":"Identification of TRAM as a sorting adaptor that directly binds MyD88-TIR to mediate IL-18 signal transduction resolved a missing link in how IL-18R engagement couples to downstream NF-κB activation.","evidence":"In vitro protein interaction assay, TRAM KO mice, RNAi knockdown, live cell co-localization imaging","pmids":["22685567"],"confidence":"High","gaps":["Structural basis of TRAM–MyD88 interaction at the IL-18R complex not resolved","Whether TRAM is required in all IL-18-responsive cell types not tested"]},{"year":2014,"claim":"Crystal structures of IL-18 bound to IL-18Rα established that electrostatic surface complementarity determines receptor specificity within the IL-1 family, providing a structural framework for understanding IL-18 signaling and decoy receptor (IL-18BP) inhibition.","evidence":"X-ray crystallography of IL-18/IL-18Rα ectodomain complex","pmids":["25261253"],"confidence":"High","gaps":["Full ternary complex with IL-18Rβ not structurally resolved","Conformational changes upon signalosome assembly not captured"]},{"year":2015,"claim":"Genetic epistasis in NLRP1 and IL-18 mutant mice established a specific NLRP1→caspase-1→IL-18 axis preventing obesity, while conditional knockout studies revealed that epithelial IL-18 signaling inhibits goblet cell maturation and that IL-18BP is a critical in vivo brake on this process.","evidence":"NLRP1 KO, activating-mutation knock-in, and IL-18 KO mice with metabolic phenotyping; conditional epithelial IL-18R1 and IL-18BP KO mice with DSS colitis and transcriptomics","pmids":["26603191","26638073"],"confidence":"High","gaps":["Precise transcriptional targets by which IL-18 suppresses goblet cell differentiation incompletely defined","Whether NLRP1 vs. NLRP3 pathway dominance is tissue-specific remains unclear"]},{"year":2020,"claim":"Engineering of decoy-resistant IL-18 (DR-18) that evades IL-18BP blockade demonstrated that IL-18BP is the dominant barrier to IL-18 anti-tumor activity, and that enteric neuron-derived IL-18 is the non-redundant source for intestinal goblet cell antimicrobial defense, revealing cell-type-specific IL-18 sourcing.","evidence":"Directed evolution of DR-18 with tumor models and CD8+ T cell subset analysis; cell-type-specific conditional IL-18 KO mice (neuron, immune, epithelial) with Salmonella infection and scRNA-seq","pmids":["32581358","31923399"],"confidence":"High","gaps":["Mechanism of IL-18 release from enteric neurons not defined","DR-18 clinical translation and potential toxicities not evaluated"]},{"year":2021,"claim":"Cryo-EM structure of the GSDMD pore revealed that electrostatic charge filtering selectively permits passage of mature (positively charged) IL-18 over the negatively charged precursor, establishing the physical mechanism of IL-18 release.","evidence":"Cryo-EM of GSDMD pore/prepore, liposome permeabilization with charge-variant IL-18 species, GSDMD acidic-residue mutagenesis","pmids":["33883744"],"confidence":"High","gaps":["In vivo quantitative contribution of GSDMD pore vs. other release mechanisms not determined","Whether GSDMD selectivity operates identically across cell types not tested"]},{"year":2023,"claim":"Crystal structure of the caspase-4/pro-IL-18 complex uncovered a binary substrate-recognition mechanism—catalytic-site tetrapeptide engagement plus a unique exosite—explaining why human caspase-4/5 but not mouse caspase-11 can process pro-IL-18, and revealed autoinhibitory intramolecular interactions in the precursor that are relieved upon cleavage to generate IL-18Rα binding sites.","evidence":"Crystal structure, in vitro cleavage reconstitution, exosite mutagenesis converting caspase-11 to gain IL-18 processing, bacterial infection models","pmids":["37993714"],"confidence":"High","gaps":["Whether the exosite mechanism operates similarly for caspase-1 in vivo not directly shown","Structural basis for caspase-5 processing not independently crystallized"]},{"year":2024,"claim":"Identification of tumor-specific IL-18 alternative splicing (ΔIL-18) driven by PTBP3 recruitment via H3K36me3-MRG15, with ΔIL-18 promoting immune evasion by stabilizing PD-1, and a parallel GFPT2-O-GlcNAcylation-YBX1 transcriptional axis promoting IL-18 secretion in pancreatic cancer, expanded understanding of IL-18 regulation in the tumor microenvironment.","evidence":"mRNA-seq, luciferase splicing reporters, antisense oligonucleotides, HuPBMC mouse models, Co-IP/MS for O-GlcNAcylated YBX1, ChIP for YBX1 on IL-18 promoter","pmids":["39116343","38575607"],"confidence":"Medium","gaps":["ΔIL-18 splice isoform prevalence across cancer types not established","GFPT2-YBX1 axis not validated in non-pancreatic contexts","Independent replication of both findings pending"]},{"year":2025,"claim":"Discovery of a caspase-3-generated nuclear 15-kDa 'short IL-18' that activates a CDK8–STAT1 Ser727–ISG15 pathway to mobilize NK cell anti-tumor cytotoxicity independently of IL-18Rα established a second, receptor-independent effector arm for IL-18.","evidence":"Caspase-3 cleavage assay, subcellular fractionation/nuclear imaging, CDK8 inhibition, ISG15 ELISA, syngeneic tumor models with NK depletion, colorectal cancer patient tissue","pmids":["39891018"],"confidence":"High","gaps":["Physiological contexts beyond cancer where short IL-18 operates are unknown","Whether short IL-18 nuclear translocation uses a defined import pathway not determined","Structural basis for CDK8-STAT1 activation by short IL-18 not resolved"]},{"year":null,"claim":"Key unresolved questions include the full ternary structure of the IL-18/IL-18Rα/IL-18Rβ signalosome, the relative quantitative contributions of different inflammasomes and caspases to IL-18 processing across tissues, the molecular mechanism of IL-18 release from enteric neurons, and the in vivo functional significance of the ΔIL-18 splice isoform.","evidence":"","pmids":[],"confidence":"Low","gaps":["Full ternary IL-18 signaling complex structure not solved","Tissue-specific inflammasome hierarchy for IL-18 processing not quantitatively established","Mechanism of IL-18 release from neurons undefined","In vivo relevance of ΔIL-18 splice variant awaits independent confirmation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,2,5,6,32]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,8,26]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[28,32,39]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,3,35]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[39]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[19]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,36]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2,5,6,8,10,18,29,32,39]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,8,9,20,24,26]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,11,28,34,38]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,25,35,36]}],"complexes":[],"partners":["IL18R1","IL18RAP","IL18BP","CASP1","CASP4","GSDMD","MYD88","TICAM2"],"other_free_text":[]},"mechanistic_narrative":"IL-18 is a pleiotropic pro-inflammatory cytokine of the IL-1 family that orchestrates innate and adaptive immune responses—most prominently IFN-γ production—while also regulating metabolic homeostasis, intestinal epithelial goblet cell maturation, and anti-tumor immunity. Synthesized as an inactive 24-kDa precursor constitutively present in most cell types, pro-IL-18 is processed to its mature 18-kDa form primarily by caspase-1 within NLRP1/NLRP3/NLRC4 inflammasomes, and alternatively by caspase-4/5 via an exosite-dependent mechanism or by granzyme B; the mature form is selectively released through electrostatically filtering GSDMD pores whose negative conduit charge preferentially passes the positively charged mature cytokine [PMID:8999548, PMID:37993714, PMID:33883744]. Mature IL-18 signals through the IL-18Rα/IL-18Rβ heterodimer, recruiting MyD88 via the sorting adaptor TRAM to activate NF-κB, AP-1, MAPK (ERK/PI3K-Akt), and STAT1 pathways, thereby synergizing with IL-12 to induce IFN-γ in NK cells, T cells, and B cells, activating neutrophils, promoting dendritic cell maturation, and—in enteric neurons—driving goblet cell antimicrobial peptide production [PMID:7477296, PMID:8766574, PMID:22685567, PMID:31923399, PMID:26638073]. A distinct caspase-3-generated 15-kDa nuclear 'short IL-18' activates an IL-18Rα-independent CDK8–STAT1 Ser727–ISG15 pathway that mobilizes NK cell anti-tumor cytotoxicity, while the secreted decoy receptor IL-18BP serves as the dominant negative regulator of canonical extracellular IL-18 bioactivity [PMID:39891018, PMID:32581358]."},"prefetch_data":{"uniprot":{"accession":"Q14116","full_name":"Interleukin-18","aliases":["Iboctadekin","Interferon gamma-inducing factor","IFN-gamma-inducing factor","Interleukin-1 gamma","IL-1 gamma"],"length_aa":193,"mass_kda":22.3,"function":"Pro-inflammatory cytokine primarily involved in epithelial barrier repair, polarized T-helper 1 (Th1) cell and natural killer (NK) cell immune responses (PubMed:10653850). Upon binding to IL18R1 and IL18RAP, forms a signaling ternary complex which activates NF-kappa-B, triggering synthesis of inflammatory mediators (PubMed:14528293, PubMed:25500532, PubMed:37993714). Synergizes with IL12/interleukin-12 to induce IFNG synthesis from T-helper 1 (Th1) cells and natural killer (NK) cells (PubMed:10653850). Involved in transduction of inflammation downstream of pyroptosis: its mature form is specifically released in the extracellular milieu by passing through the gasdermin-D (GSDMD) pore (PubMed:33883744)","subcellular_location":"Cytoplasm, cytosol; Secreted","url":"https://www.uniprot.org/uniprotkb/Q14116/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL18","classification":"Not Classified","n_dependent_lines":24,"n_total_lines":1208,"dependency_fraction":0.019867549668874173},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL18","total_profiled":1310},"omim":[{"mim_id":"620796","title":"PROTEASOME-ASSOCIATED AUTOINFLAMMATORY SYNDROME 6; PRAAS6","url":"https://www.omim.org/entry/620796"},{"mim_id":"619858","title":"AUTOINFLAMMATORY-PANCYTOPENIA SYNDROME; AIPCS","url":"https://www.omim.org/entry/619858"},{"mim_id":"619802","title":"IMMUNODEFICIENCY 97 WITH AUTOINFLAMMATION; IMD97","url":"https://www.omim.org/entry/619802"},{"mim_id":"618998","title":"IMMUNE DYSREGULATION AND SYSTEMIC HYPERINFLAMMATION SYNDROME; IMDYSHI","url":"https://www.omim.org/entry/618998"},{"mim_id":"618803","title":"RESPIRATORY PAPILLOMATOSIS, JUVENILE RECURRENT, CONGENITAL; JRRP","url":"https://www.omim.org/entry/618803"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"esophagus","ntpm":117.0},{"tissue":"skin 1","ntpm":140.9}],"url":"https://www.proteinatlas.org/search/IL18"},"hgnc":{"alias_symbol":["IGIF","IL1F4","IL-1g","IL-18"],"prev_symbol":[]},"alphafold":{"accession":"Q14116","domains":[{"cath_id":"2.80.10.50","chopping":"37-190","consensus_level":"high","plddt":94.2203,"start":37,"end":190}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14116","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14116-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14116-F1-predicted_aligned_error_v6.png","plddt_mean":89.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL18","jax_strain_url":"https://www.jax.org/strain/search?query=IL18"},"sequence":{"accession":"Q14116","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14116.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14116/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14116"}},"corpus_meta":[{"pmid":"24115947","id":"PMC_24115947","title":"Interleukin-18 and IL-18 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America","url":"https://pubmed.ncbi.nlm.nih.gov/18523012","citation_count":379,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29326099","id":"PMC_29326099","title":"Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome.","date":"2018","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/29326099","citation_count":319,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9108085","id":"PMC_9108085","title":"Interleukin 18 together with interleukin 12 inhibits IgE production by induction of interferon-gamma production from activated B cells.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9108085","citation_count":309,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12759422","id":"PMC_12759422","title":"IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells.","date":"2003","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/12759422","citation_count":302,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10227975","id":"PMC_10227975","title":"IL-18 is a potent coinducer of IL-13 in NK and T cells: a new potential role for IL-18 in modulating the immune response.","date":"1999","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10227975","citation_count":281,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21836147","id":"PMC_21836147","title":"Postoperative biomarkers predict acute kidney injury and poor outcomes after pediatric cardiac surgery.","date":"2011","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/21836147","citation_count":281,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15802534","id":"PMC_15802534","title":"NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1.","date":"2005","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15802534","citation_count":275,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"36032110","id":"PMC_36032110","title":"Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36032110","citation_count":274,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10639148","id":"PMC_10639148","title":"IL-18 regulates IL-1beta-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1.","date":"2000","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10639148","citation_count":273,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10653850","id":"PMC_10653850","title":"IL-12 synergizes with IL-18 or IL-1beta for IFN-gamma production from human T cells.","date":"2000","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10653850","citation_count":273,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48819,"output_tokens":8734,"usd":0.138734},"stage2":{"model":"claude-opus-4-6","input_tokens":12733,"output_tokens":3139,"usd":0.21321},"total_usd":0.803517,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of 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Crystal structure of the caspase-4–pro-IL-18 complex reveals a two-site (binary) substrate-recognition mechanism: the catalytic pocket engages the tetrapeptide cleavage site, and a unique exosite binds a structure formed jointly by the propeptide and post-cleavage-site sequences. The same binary recognition is used by caspase-5 and caspase-1. The pro-IL-18 structure features autoinhibitory interactions between the propeptide and post-cleavage-site region that prevent IL-18Rα binding; cleavage induces conformational changes generating two receptor-binding sites.\",\n      \"method\": \"Crystal structure of caspase-4–pro-IL-18 complex; in vitro cleavage assays; active-site mutagenesis restoring caspase-11 activity; bacterial infection models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus in vitro reconstitution plus mutagenesis in a single study\",\n      \"pmids\": [\"37993714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL-18 is synthesized as an inactive 24-kDa precursor (pro-IL-18) that requires caspase-1 (IL-1β-converting enzyme, ICE) cleavage to generate the active 18-kDa mature form. Unlike IL-1β, the pro-IL-18 precursor is constitutively present in nearly all cells. The activity of IL-18 is balanced by a high-affinity naturally occurring IL-18 binding protein (IL-18BP) that neutralizes free IL-18.\",\n      \"method\": \"Western blot demonstrating precursor vs. mature forms; caspase-1-deficient cell studies; binding assays for IL-18BP\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — extensively replicated across many labs, synthesized in comprehensive review\",\n      \"pmids\": [\"24115947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of IL-18 bound to the ectodomain of its primary receptor IL-18Rα reveals that surface charge complementarity determines ligand-binding specificity of primary receptors in the IL-1 receptor family; the IL-18 signaling complex adopts an architecture similar to other agonistic cytokines in the IL-1 family.\",\n      \"method\": \"X-ray crystallography of IL-18/IL-18Rα ectodomain complex\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional modeling\",\n      \"pmids\": [\"25261253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In cancer cells, caspase-3 cleaves IL-18 to generate a 15-kDa 'short IL-18' form distinct from the caspase-1-generated 18-kDa mature form. Short IL-18 is not secreted and does not bind IL-18Rα; instead it translocates to the nucleus, where it facilitates STAT1 phosphorylation at Ser727 via CDK8, enhancing ISG15 expression and secretion, which mobilizes NK cells to eliminate tumors.\",\n      \"method\": \"In vitro caspase-3 cleavage assays; nuclear fractionation; STAT1 phosphorylation assays; CDK8 interaction studies; syngeneic tumor mouse models; patient colorectal cancer tissue analysis\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including reconstitution, signaling pathway dissection, and in vivo models\",\n      \"pmids\": [\"39891018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRAM (TRIF-related adaptor molecule/TICAM-2) directly interacts with MyD88-TIR domain in vitro and functions as a sorting adaptor for MyD88 in IL-18 signal transduction. TRAM-deficient mice show impaired IL-18 signaling. Live-cell imaging showed co-localized membrane accumulation of MyD88 and TRAM. TRAM binding sites on MyD88-TIR overlap with Mal binding sites.\",\n      \"method\": \"In vitro TIR-domain binding assay; RNAi knockdown in cells; TRAM-deficient mouse IL-18 signaling assays; live-cell fluorescence imaging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods but single lab\",\n      \"pmids\": [\"22685567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL-18 signals through a receptor system analogous to IL-1R, using MyD88 as a downstream adaptor, and in collaboration with IL-12 drives IFN-γ production and Th1 responses. IL-18-deficient mice showed defective NK cell activity and Th1 responses in vivo.\",\n      \"method\": \"IL-18 knockout mice; NK cell cytotoxicity assays; cytokine production assays\",\n      \"journal\": \"Current opinion in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with defined cellular phenotypes, replicated across labs\",\n      \"pmids\": [\"10679398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-18 produced from the NLRP1 inflammasome (via caspase-1 activation) prevents obesity and metabolic syndrome. Mice lacking NLRP1 phenocopy IL-18-deficient mice with spontaneous obesity; mice with activating NLRP1 mutations have increased IL-18 and decreased adiposity. Lethal cachexia from NLRP1 gain-of-function on HFD is rescued by IL-18 genetic deletion, placing NLRP1 upstream of IL-18 in a defined metabolic pathway.\",\n      \"method\": \"NLRP1 knockout and gain-of-function mice; IL-18 knockout mice; genetic epistasis (NLRP1 activating mutation × IL-18 deletion); diet-induced obesity models\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic epistasis with multiple orthogonal mouse models in single study\",\n      \"pmids\": [\"26603191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-18 signaling in intestinal epithelial cells (IEC) controls barrier integrity in colitis by inhibiting goblet cell maturation through regulation of the transcriptional program governing goblet cell development. Deletion of Il18 or Il18r1 in IEC protects from colitis; deletion of IL-18 negative regulator Il18bp causes severe colitis with goblet cell loss, rescued by simultaneous Il18r deletion in IEC, demonstrating that colitis severity is controlled at the level of epithelial IL-18 signaling.\",\n      \"method\": \"Conditional knockout mice (Il18-ΔEC, Il18r1-ΔEC, Il18bp−/−); epistasis rescue experiments (Il18bp−/−;Il18r-ΔEC); transcriptional profiling of goblet cell development\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — rigorous genetic epistasis with multiple conditional knockouts, published in Cell\",\n      \"pmids\": [\"26638073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Enteric neurons are a non-redundant source of IL-18 that specifically controls homeostatic goblet cell antimicrobial protein (AMP) production. Deletion of IL-18 from enteric neurons alone (but not from immune or epithelial cells) renders mice susceptible to invasive Salmonella typhimurium infection. Identified via confocal microscopy, smFISH, and RNA/single-cell sequencing.\",\n      \"method\": \"Cell-type-specific IL-18 conditional knockout (enteric neurons, immune cells, epithelial cells); confocal microscopy; smFISH; RNA-seq and single-cell sequencing; Salmonella infection model\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches including cell-type-specific deletion with specific phenotypic rescue\",\n      \"pmids\": [\"31923399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-18BP is frequently upregulated in diverse human and mouse tumors and acts as a secreted immune checkpoint that limits anti-tumor activity of IL-18. A directed-evolution-engineered 'decoy-resistant' IL-18 (DR-18) that maintains signaling but is impervious to IL-18BP inhibition promotes effector CD8+ T cells, reduces TOX+ exhausted CD8+ T cells, expands TCF1+ stem-like precursor CD8+ T cells, and enhances NK cell activity against anti-PD-1-resistant MHC-I-loss tumors.\",\n      \"method\": \"Directed protein evolution; mouse tumor models; flow cytometry of T cell and NK cell phenotypes; IL-18BP binding assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — engineered mutant with in vitro binding characterization plus multiple in vivo tumor models\",\n      \"pmids\": [\"32581358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Inflammasome (NLRP3)-dependent caspase-1 cleavage and activation of IL-18, but not IL-1β, is the critical upstream regulator of chemokine expression in the myocardium upon acute β-adrenergic receptor (β1-AR) stimulation. IL-18 drives chemokine production, macrophage infiltration, and cardiac fibrosis downstream of β1-AR–ROS signaling. Genetic deletion of IL-18 or NLRP3 attenuated these effects.\",\n      \"method\": \"Cytokine array; IL-18 knockout and NLRP3 knockout mice; IL-18 neutralizing antibody; isoproterenol mouse model; cardiac histology\",\n      \"journal\": \"European heart journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockouts plus pharmacological neutralization with specific pathway placement\",\n      \"pmids\": [\"28549109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Gasdermin D (GSDMD), activated in intestinal epithelial cells by dysregulated commensal E. coli during colitis, promotes IL-18 release (without affecting IL-18 transcript or maturation level). Released IL-18 mediates goblet cell loss to induce colitis development.\",\n      \"method\": \"GSDMD knockout mice; cell-type-specific GSDMD deletion (IEC vs. immune cells); DSS-colitis model; IL-18 measurement at transcript, protein, and secretion levels\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockouts with mechanistic distinction between maturation and secretion, single lab\",\n      \"pmids\": [\"34721422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Granzyme B released from CD8+ CTLs cleaves keratinocyte pro-IL-18 into its active form in a similar fashion to caspase-1. In co-culture of GrB+/caspase-1− CD8+ T cells with IFN-γ-treated HaCaT keratinocytes, GrB transferred into keratinocytes and mature IL-18 levels increased in the supernatant.\",\n      \"method\": \"Co-culture of primary CD8+ T cells with HaCaT keratinocytes; flow cytometry for GrB uptake; ELISA for mature IL-18; PCR for endogenous GrB expression\",\n      \"journal\": \"Archives of dermatological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional cell-based assay demonstrating GrB as an IL-18-converting enzyme, single lab\",\n      \"pmids\": [\"23820889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human neutrophils constitutively express IL-18Rα and IL-18Rβ, enabling rapid IL-18 responses. IL-18 induces cytokine/chemokine release (protein synthesis-dependent), upregulates CD11b, induces granule release, and enhances the respiratory burst in response to fMLP. In vivo, IL-18 promotes neutrophil accumulation and IL-18 neutralization suppresses footpad inflammation.\",\n      \"method\": \"Flow cytometry for IL-18R expression; protein synthesis inhibitor experiments; respiratory burst assays; in vivo IL-18 administration and neutralization\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro and in vivo assays in single study\",\n      \"pmids\": [\"11509635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IL-18 promotes neutrophil accumulation in vivo via a TNF-α–leukotriene B4 (LTB4) axis: rIL-18 i.p. induces peritoneal LTB4 production and neutrophil influx blocked by LTB4 synthesis inhibitor MK-886 or anti-TNF-α antibody; IL-18 fails to recruit neutrophils in TNFRp55−/− mice. Human neutrophils activated by IL-18 produce LTB4.\",\n      \"method\": \"In vivo IL-18 administration with pharmacological inhibitors; TNFRp55 knockout mice; LTB4 measurement; collagen-induced arthritis model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout plus pharmacological epistasis replicated in human cells and mouse arthritis model\",\n      \"pmids\": [\"12847274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"During mouse CMV infection, NK cells require IL-18–MyD88 signaling (but not IL-1R) for optimal primary expansion. IL-12 signaling and STAT4 in activated NK cells increase MyD88 expression, which mediates downstream IL-18 signaling; this axis is required for primary but not memory NK cell responses.\",\n      \"method\": \"MyD88-deficient and IL-1R-deficient mice; MCMV infection model; NK cell expansion assays; STAT4 knockout studies\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in infection model, single lab\",\n      \"pmids\": [\"25589075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Bcl6 functions as a transcriptional repressor of the IL-18 gene. Bcl6 binds a specific Bcl6-binding DNA sequence (IL-18BS) in the IL-18 promoter in resting macrophages (demonstrated by gel retardation and chromatin immunoprecipitation). IL-18BS is required for Bcl6-mediated repression in luciferase reporter assays. LPS stimulation diminishes Bcl6 binding without altering Bcl6 protein levels, suggesting post-translational modification.\",\n      \"method\": \"Bcl6 knockout macrophages; dominant-negative Bcl6 transfection; gel retardation assay; ChIP; luciferase reporter assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP plus reporter assay plus genetic loss-of-function converging on same conclusion\",\n      \"pmids\": [\"12817026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IL-18 enhances IFN-γ-induced CXCL9, CXCL10, and CXCL11 production in human keratinocytes by activating NF-κB, STAT1, and IRF-1 through PI3K/Akt and MEK/ERK pathways. IL-18 induces ERK and Akt phosphorylation; antisense knockdown of NF-κB subunits or STAT1 suppresses chemokine production.\",\n      \"method\": \"Antisense oligonucleotides; pathway inhibitors (PI3K, p38 MAPK, MEK); Western blot for kinase phosphorylation; ELISA for chemokine production\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple signaling inhibitors and genetic knockdowns in human cells, single lab\",\n      \"pmids\": [\"17274000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-18 downregulates type I and III collagen gene expression and production in human dermal fibroblasts via ERK phosphorylation and the transcription factor Ets-1. siRNA knockdown of Ets-1 abolishes IL-18-mediated collagen suppression; ERK inhibitor PD98059 blocks the inhibitory effect. IL-18 also inhibits TGF-β-induced collagen gene expression.\",\n      \"method\": \"siRNA knockdown of Ets-1; ERK inhibitor PD98059; Western blot for phospho-ERK; RT-PCR and ELISA for collagen expression\",\n      \"journal\": \"Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA and pharmacological inhibition with signaling readout, single lab\",\n      \"pmids\": [\"19865096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-18 induces osteopontin (OPN) expression in cardiac fibroblasts, which mediates interstitial fibrosis and diastolic dysfunction. IL-18 receptor blockade abolishes IL-18-induced OPN upregulation in fibroblasts. IRF1 mutation or IRF1 siRNA decreases IL-18 and OPN expression; IRF1-mutant mice show downregulated IL-18/OPN, reduced fibrosis, and improved LV function under pressure overload.\",\n      \"method\": \"Primary cardiac fibroblast cultures; IL-18 receptor neutralizing antibody; IRF1 siRNA and mutant mice; echocardiography; pressure overload model\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro and in vivo approaches with genetic component, single lab\",\n      \"pmids\": [\"19429811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL-18 mediates profibrotic renal tubular cell injury via STAT3 activation. In vitro, IL-18 stimulates HK-2 cells to increase phospho-STAT3, SOCS3, α-SMA, collagen III expression, collagen production, and apoptosis; STAT3 inhibitor S3I-201 significantly diminishes these effects. In vivo, IL-18 neutralization reduces p-STAT3 and SOCS3 expression in obstructed kidneys.\",\n      \"method\": \"IL-18 stimulation of HK-2 cells; STAT3 inhibitor S3I-201; IL-18-binding protein transgenic mice; Western blot and immunohistochemistry\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibition plus transgenic mouse model, single lab\",\n      \"pmids\": [\"23904224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IL-18 neutralization protects against LPS-induced myocardial dysfunction, associated with reduced myocardial IL-1β production (65% reduction) and decreased ICAM-1/VCAM-1 expression. TNF-α levels were not influenced by IL-18 neutralization, indicating that IL-18 mediates cardiac dysfunction via IL-1β and adhesion molecules rather than TNF-α.\",\n      \"method\": \"Neutralizing anti-IL-18 antibody in LPS-treated mice; Langendorff isolated heart preparation for LVDP; ELISA for cytokines; Western blot for adhesion molecules\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — specific neutralization with functional cardiac readout and pathway dissection, single lab\",\n      \"pmids\": [\"12124212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Langerhans cell-derived IL-18 contributes to contact hypersensitivity (CHS) initiation. Caspase-1 is required for mature IL-18 production in draining lymph nodes; caspase-1−/− lymph node cells show impaired IFN-γ production restored by exogenous IL-18. CHS responses are significantly inhibited by neutralizing anti-IL-18 Ab and in caspase-1−/− mice.\",\n      \"method\": \"Murine CHS model; caspase-1 knockout mice; anti-IL-18 neutralizing antibody; rescue with exogenous IL-18\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological approaches with functional rescue, single lab\",\n      \"pmids\": [\"11907086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-18-mediated neonatal sepsis lethality depends on IL-1R1 signaling and IL-17A production by intestinal γδT cells and Ly6G+ myeloid cells, independently of adaptive immunity. Blocking IL-17A reduces IL-18-potentiated mortality, establishing an IL-18/IL-1/IL-17A signaling axis in neonatal sepsis.\",\n      \"method\": \"IL-18 knockout neonatal mice; IL-18 administration; IL-1R1 knockout mice; IL-17A neutralization; polymicrobial sepsis model; genome-wide blood mRNA analysis\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple knockout lines and cytokine neutralization, single lab\",\n      \"pmids\": [\"27114524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Unopposed IL-18 signaling (in IL-18BP-deficient mice) upon TLR9 stimulation leads to severe macrophage activation syndrome (MAS) with elevated free IL-18 and IFN-γ. Blocking IL-18 receptor signaling attenuates MAS severity and IFN-γ responses. Blocking IFN-γ has comparable effects, placing IL-18 upstream of IFN-γ in MAS pathogenesis.\",\n      \"method\": \"IL-18BP knockout mice; TLR9 stimulation (CpG); IL-18 receptor blocking antibody; IFN-γ neutralizing antibody; clinical MAS parameter measurement\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic model plus two independent cytokine blockade experiments establishing epistatic pathway\",\n      \"pmids\": [\"29295842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-18 enhances thrombospondin-1 (TSP-1) production in human gastric cancer cells via the JNK signaling pathway; IL-18 induces JNK phosphorylation and JNK-specific inhibitor SP600125 blocks IL-18-enhanced TSP-1 expression.\",\n      \"method\": \"RT-PCR and ELISA for TSP-1; JNK inhibitor SP600125; Western blot for phospho-JNK\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single pharmacological inhibitor approach, single lab\",\n      \"pmids\": [\"16650813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL-18 activates AP-1 and NF-κB transcription factors in CD4+ T lymphocytes in a time- and dose-dependent manner, leading to IL-2 gene transcription and IL-2 protein production. Depletion of IL-18 from sarcoid epithelial lining fluid using neutralizing antibodies abrogates AP-1/NF-κB activation and IL-2 production.\",\n      \"method\": \"Transcription factor activity assays; IL-18 neutralizing antibody depletion; IL-2 mRNA and protein measurement in Jurkat T cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assays with neutralization and signaling readouts, single lab\",\n      \"pmids\": [\"11035116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IL-15 triggers IL-18 production to mediate neutrophil migration. In IL-18-deficient mice, IL-15-induced neutrophil migration is abrogated. IL-15 induces IL-18 which then drives production of MIP-2, MIP-1α, TNF-α, and LTB4 for neutrophil recruitment, establishing a sequential IL-15→IL-18→MIP-2/MIP-1α/TNF-α/LTB4 cascade.\",\n      \"method\": \"IL-18 knockout mice; cytokine/chemokine measurement; pharmacological inhibitors; antigen-specific (OVA) peritoneal inflammation model\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with defined sequential cascade, single lab\",\n      \"pmids\": [\"17979156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NLRP3 activation in cholangiocytes specifically stimulates IL-18 (but not IL-1β or IL-6) production. NLRP3 activation decreases expression of tight junction proteins Zonulin-1 and E-cadherin, impairing epithelial barrier integrity; NLRP3 knockdown increases cholangiocyte monolayer permeability.\",\n      \"method\": \"siRNA NLRP3 knockdown in cholangiocytes; NLRP3 knockout mice (DDC model); LPS+ATP stimulation; permeability assays; cytokine ELISA\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and siRNA approaches with functional epithelial barrier readout, single lab\",\n      \"pmids\": [\"27912077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"miR-379 and miR-411 (same chromosome 14q32 cluster) directly target the IL-18 gene. Luciferase reporter assays demonstrate direct targeting of IL-18 3'UTR. Introduction of miR-379+miR-411 mimics, or IL-18 silencing, suppresses invasive capacity of MPM cells and increases chemotherapy sensitivity.\",\n      \"method\": \"Luciferase reporter assay with IL-18 3'UTR; miRNA mimic transfection; IL-18 siRNA; invasion assays; drug sensitivity assays\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct luciferase reporter validation of miRNA targeting plus functional cellular assays\",\n      \"pmids\": [\"25231602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GFPT2-mediated O-GlcNAcylation of YBX1 causes its nuclear translocation, where YBX1 acts as a transcription factor to promote IL-18 transcription in pancreatic cancer cells, linking the hexosamine biosynthesis pathway to IL-18-mediated immune microenvironment regulation.\",\n      \"method\": \"Co-IP and protein mass spectrometry identifying O-GlcNAcylated YBX1; cellular proteomics identifying IL-18 as key downstream target; transcription factor assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with mass spectrometry plus proteomics and functional transcription assays, single lab\",\n      \"pmids\": [\"38575607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTBP3 promotes exon skipping of IL-18 pre-mRNA to generate a tumor-specific ΔIL-18 isoform. H3K36me3 recruits PTBP3 via MRG15, coupling IL-18 transcription and alternative splicing. SETD2-bound hnRNPL competes with PTBP3 binding to IL-18 pre-mRNA. ΔIL-18 promotes immune escape by downregulating FBXO38 transcription in CD8+ T cells, reducing PD-1 ubiquitin-mediated degradation.\",\n      \"method\": \"Multi-omics analysis; RNA splicing assays; antisense oligonucleotide blocking; HuPBMC mouse tumor model; ChIP for H3K36me3; Co-IP for PTBP3/MRG15/hnRNPL\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-omics with Co-IP and functional in vivo validation, single lab\",\n      \"pmids\": [\"39116343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IL-18 regulates SCF (stem cell factor) expression in B16F10 melanoma cells via reactive oxygen intermediates (ROI) and p38 MAPK. IL-18 antisense transfection reduces SCF; exogenous IL-18 restores it. Antioxidant NAC and p38 MAPK inhibitor SB203580 block IL-18-enhanced SCF production.\",\n      \"method\": \"IL-18 antisense transfection; pharmacological inhibitors (NAC, SB203580); RT-PCR, FACS, and ELISA for SCF\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — antisense and pharmacological inhibitors but single lab and limited orthogonal validation\",\n      \"pmids\": [\"15585325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A highly stable IL-18 protein was engineered by replacing cysteine residues with serine based on the 3D structure and receptor-binding mode, retaining full biological IFN-γ-inducing activity while preventing multimerization/inactivation.\",\n      \"method\": \"Structure-guided mutagenesis; recombinant protein production; biological activity assay (IFN-γ induction)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — structure-guided mutagenesis with functional validation\",\n      \"pmids\": [\"15047165\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-18 is an IL-1 family cytokine synthesized as an autoinhibited 24-kDa pro-form constitutively present in most cells; it is activated by caspase-1 (canonical inflammasome), caspase-4/5 (noncanonical inflammasome, via a two-site binary recognition mechanism also used by caspase-1), and granzyme B, all cleaving the same tetrapeptide site and inducing conformational changes that generate the IL-18Rα-binding surfaces; the resulting 18-kDa mature cytokine signals through IL-18Rα/IL-18Rβ using MyD88 (assisted by the sorting adaptor TRAM) to activate NF-κB, STAT1, ERK/Akt, and AP-1, driving IFN-γ production from NK and T cells, neutrophil activation via TNF-α/LTB4, and epithelial goblet cell regulation; its activity is tightly buffered by the high-affinity decoy receptor IL-18BP; additionally, caspase-3 cleavage generates a distinct nuclear 15-kDa 'short IL-18' that signals via CDK8–STAT1(Ser727)–ISG15 to mobilize NK cells independently of IL-18Rα.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"IL-18 (originally called IGIF) was cloned as a novel cytokine that induces IFN-γ production by T cells and enhances NK cell cytotoxicity; the gene encodes a 192-amino acid precursor protein with a mature form of 157 amino acids, with no homology to other known cytokines at the time.\",\n      \"method\": \"cDNA cloning, recombinant protein expression, IFN-γ induction assay in spleen cells, NK cytotoxicity assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original cloning paper with functional validation, foundational discovery replicated extensively\",\n      \"pmids\": [\"7477296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Human IL-18 cDNA was cloned; recombinant human IL-18 induced IFN-γ production in mitogen-stimulated PBMC, enhanced NK cell cytotoxicity, augmented GM-CSF production, and decreased IL-10 production, establishing it as a pleiotropic cytokine designated IL-18.\",\n      \"method\": \"cDNA cloning from human liver library, recombinant protein expression in E. coli, PBMC stimulation assays, ELISA\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — recombinant protein with multiple functional assays, foundational characterization paper\",\n      \"pmids\": [\"8666798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"IL-18 (IGIF) synergizes with IL-12 to induce IFN-γ production from human T cells; IL-18 promotes T cell proliferation through an IL-2-dependent pathway and enhances Th1 cytokine production (IFN-γ, IL-2, GM-CSF) without affecting IL-4 or IL-10, demonstrating a distinct pathway from IL-12.\",\n      \"method\": \"Anti-CD3 stimulation of human T cells, ELISA, CTLL-2 bioassay, neutralizing antibodies\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, foundational synergy paper replicated across many subsequent studies\",\n      \"pmids\": [\"8766574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Caspase-1 (ICE) cleaves the pro-IL-18 precursor at the authentic processing site with high efficiency, generating the active mature form; caspase-1-deficient Kupffer cells synthesized pro-IL-18 but failed to process it, and caspase-1-deficient mice showed diminished serum IFN-γ and IL-18 after LPS challenge.\",\n      \"method\": \"In vitro cleavage assay with recombinant ICE, ICE-knockout mice, LPS/P. acnes challenge model, ELISA\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution plus knockout mouse validation, widely replicated\",\n      \"pmids\": [\"8999548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The human IL-18 receptor (IL-18Rα) was purified and identified as IL-1Rrp (IL-1 receptor-related protein); IL-18 binding to L428 cells had a Kd of ~18.5 nM with ~18,000 sites/cell; IL-18 binding was not competed by IL-1β; expression of IL-1Rrp cDNA in COS-1 cells conferred both IL-18 binding and signal transduction capacity.\",\n      \"method\": \"Radioligand binding assay, receptor purification by lectin and mAb chromatography, COS-1 cell expression system, N-terminal peptide sequencing\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — receptor purification, binding kinetics, and functional reconstitution in heterologous cells\",\n      \"pmids\": [\"9325300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"IL-18 together with IL-12 induces IFN-γ production from activated B cells, which in turn inhibits IL-4-dependent IgE and IgG1 production and enhances IgG2a production; B cells from normal mice can become IFN-γ-producing cells in IFN-γ-deficient host mice in response to IL-12 plus IL-18.\",\n      \"method\": \"In vitro anti-CD40/IL-4 stimulation, ELISA, in vivo mouse models (N. brasiliensis, anti-IgD), adoptive transfer into IFN-γ KO mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro and in vivo methods demonstrating B cell IFN-γ production downstream of IL-18+IL-12\",\n      \"pmids\": [\"9108085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"IL-18 can act as a potent co-inducer of IL-13 in NK and T cells when combined with IL-2 (independent of IFN-γ), demonstrating that IL-18 can promote Th2-type cytokine production in addition to its Th1-inducing activities, depending on the cytokine milieu.\",\n      \"method\": \"NK and T cell stimulation assays, ELISA, Northern blot, IFN-γ knockout mouse cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell types and IFN-γ KO controls establishing IFN-γ-independent IL-13 induction\",\n      \"pmids\": [\"10227975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Bioactive (mature) IL-18 is predominantly present in Crohn's disease mucosa as an 18-kDa form, whereas in controls it exists as the 24-kDa precursor; active caspase-1 (ICE) p20 subunit is expressed in IBD samples, and antisense knockdown of IL-18 in CD LPMC reduced IFN-γ expression, placing IL-18 upstream of IFN-γ production in CD.\",\n      \"method\": \"Western blot, RT-PCR, antisense oligonucleotide knockdown, IFN-γ ELISA\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods but in a disease context without reconstitution; causal link established by antisense knockdown\",\n      \"pmids\": [\"10384110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL-18 signals through a receptor system (IL-18Rα and IL-18Rβ) analogous to the IL-1 receptor, activating the same downstream signal transduction pathway including NF-κB; IL-18-deficient mice have impaired NK cell activity and in vivo Th1 responses.\",\n      \"method\": \"IL-18 knockout mice, NK cytotoxicity assays, cytokine measurements\",\n      \"journal\": \"Current opinion in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knockout mouse studies replicated across multiple labs establishing IL-18R signaling pathway\",\n      \"pmids\": [\"10679398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL-18 activates NF-κB and AP-1 in CD4+ T cells (Jurkat cells), driving IL-2 gene transcription and protein production; depletion of IL-18 from sarcoid epithelial lining fluid with neutralizing antibodies abrogated AP-1/NF-κB activation and IL-2 production, positioning IL-18 upstream of T cell IL-2 production.\",\n      \"method\": \"Transcription factor EMSA, luciferase/reporter assays, neutralizing antibody depletion, ELISA, Jurkat cell stimulation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods in cell-based system; neutralizing antibody depletion provides functional validation\",\n      \"pmids\": [\"11035116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human peripheral blood neutrophils constitutively express IL-18Rα and IL-18Rβ; IL-18 induces cytokine/chemokine release (protein synthesis-dependent), up-regulates CD11b, induces granule release, and enhances the respiratory burst after fMLP, but does not affect neutrophil apoptosis; IL-18 administration promoted neutrophil accumulation in vivo and IL-18 neutralization suppressed carrageenan-induced footpad inflammation.\",\n      \"method\": \"Flow cytometry, ELISA, myeloperoxidase assay, in vivo mouse models, neutralizing antibodies\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro functional assays plus in vivo neutralization confirming neutrophil-activating role\",\n      \"pmids\": [\"11509635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IL-18 expression in human atherosclerotic plaque occurs predominantly as the mature 18-kDa form in macrophages; endothelial cells, smooth muscle cells, and macrophages all constitutively express functional IL-18Rα/β complex; IL-18 signaling in these vascular cells induces IL-6, IL-8, ICAM-1, and MMP-1/-9/-13 expression, and IL-18 plus IL-12 induces IFN-γ in smooth muscle cells (but not endothelial cells).\",\n      \"method\": \"Immunohistochemistry, Western blot, in vitro cell stimulation, ELISA, RT-PCR\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell types, orthogonal methods, functional receptor signaling validated in primary and cultured vascular cells\",\n      \"pmids\": [\"11805151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IL-18 regulates IL-1β-dependent hepatic melanoma metastasis: B16 melanoma-conditioned medium stimulates hepatic sinusoidal endothelial cells to sequentially release TNF-α, IL-1β, and IL-18; exogenous IL-18 increases VCAM-1 expression on HSE and melanoma cell adhesion via a VCAM-1-dependent (not IL-1R or TNF-dependent) mechanism; anti-IL-18 or IL-18BP abolished this adhesion.\",\n      \"method\": \"In vitro co-culture adhesion assays, intrasplenic tumor injection model, IL-1β and caspase-1 KO mice, neutralizing antibodies, VCAM-1 blocking\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockouts plus neutralizing antibodies plus in vivo model with multiple orthogonal readouts\",\n      \"pmids\": [\"10639148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"ATP release from monocytes stimulated with microbial ligands or uric acid triggers autocrine P2X7 receptor activation, leading to K+ efflux and phospholipase A2 activation, which are required for caspase-1-dependent maturation and secretion of both IL-1β and IL-18; P2X7 antagonists or apyrase prevent IL-18 secretion.\",\n      \"method\": \"Primary human monocyte cultures, ATP measurement, P2X7 antagonists, apyrase treatment, caspase-1 inhibitors, ELISA, intracellular flow cytometry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple pharmacological interventions and a gain-of-function mutant inflammasome control establishing the ATP-P2X7-IL-18 secretion pathway\",\n      \"pmids\": [\"18523012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IL-18 activates neutrophils via TNF-α induction, which drives production of leukotriene B4 (LTB4), causing neutrophil accumulation; IL-18-induced neutrophil recruitment and LTB4 production were blocked by LTB4 synthesis inhibitor MK-886, LTB4 receptor antagonist CP-105696, anti-TNF-α antibody, and was absent in TNFRp55-/- mice.\",\n      \"method\": \"In vivo peritoneal neutrophil recruitment model, LTB4 ELISA, pharmacological inhibitors, TNFRp55 knockout mice, anti-TNF-α neutralization\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological epistasis establishing the IL-18→TNF-α→LTB4→neutrophil axis\",\n      \"pmids\": [\"12847274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Bcl6 functions as a sequence-specific transcriptional repressor of the IL-18 gene; a Bcl6-binding DNA sequence (IL-18BS) was identified upstream of exon 1 of the murine IL-18 gene and in the human IL-18 promoter; Bcl6 binding to IL-18BS was detected by gel retardation and ChIP assays and diminished after LPS stimulation; Bcl6 repressed IL-18 promoter-driven luciferase expression in an IL-18BS-dependent manner.\",\n      \"method\": \"Gel retardation (EMSA), chromatin immunoprecipitation (ChIP), luciferase reporter assay, dominant-negative transfection, Bcl6 KO macrophages, RT-PCR\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple direct biochemical methods (ChIP, EMSA, reporter assay) in both KO and dominant-negative contexts\",\n      \"pmids\": [\"12817026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Langerhans cell-derived IL-18 contributes to contact hypersensitivity initiation; mature IL-18 (requiring caspase-1 cleavage) is necessary for IL-12-stimulated IFN-γ production by lymph node cells; caspase-1-/- LN cells showed impaired IFN-γ production that was restored by exogenous IL-18; CHS was significantly inhibited by neutralizing anti-IL-18 antibody and in caspase-1-/- mice.\",\n      \"method\": \"Murine CHS model, IL-18 neutralizing antibodies, caspase-1 KO mice, in vitro IFN-γ production assays, exogenous IL-18 rescue\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout and antibody neutralization with clear rescue experiment linking caspase-1 processing to functional IL-18\",\n      \"pmids\": [\"11907086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A highly stable human IL-18 protein was generated by replacing cysteines with serines based on the 3D crystal structure and receptor-binding mechanism, retaining full biological activity, establishing that the cysteine residues are not required for function but contribute to multimerization-based inactivation.\",\n      \"method\": \"Site-directed mutagenesis, recombinant protein production, biological activity assay (IFN-γ induction), structural analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — structure-guided mutagenesis with functional validation in single study\",\n      \"pmids\": [\"15047165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-18 directly induces maturation of myeloid dendritic cells (but not differentiation of monocytes): IL-18 stimulation increased CD83, HLA-DR, and co-stimulatory molecules on monocyte-derived DCs and KG-1 cells, decreased pinocytosis, and enhanced alloreactive T cell stimulatory capacity.\",\n      \"method\": \"Flow cytometry, pinocytosis assay, mixed lymphocyte reaction, monocyte-derived DC culture\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional readouts of DC maturation in human primary cells and cell line\",\n      \"pmids\": [\"15135292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"NK cells trigger immature DCs to polarize secretory lysosomes containing IL-18 toward the NK cell contact site in a Ca2+-dependent, tubulin-mediated manner; IL-18 is released at the synaptic cleft (not diffusely), activating only the interacting NK cell; this establishes a polarized secretion mechanism for the leaderless cytokine IL-18.\",\n      \"method\": \"Confocal microscopy, lysosome tracking, Ca2+ chelation, tubulin disruption, ELISA of synaptic vs. non-synaptic fractions\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct live imaging of polarized secretion with pharmacological dissection of the Ca2+/tubulin mechanism\",\n      \"pmids\": [\"15802534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IL-18 enhances IFN-γ-induced production of CXCL9, CXCL10, and CXCL11 in human keratinocytes by activating NF-κB, STAT1, and IRF-1 through PI3K/Akt and MEK/ERK pathways; antisense oligonucleotides against NF-κB p50/p65 or STAT1 suppressed chemokine production; IL-18 induced phosphorylation of ERK and Akt.\",\n      \"method\": \"Antisense oligonucleotides, ELISA, RT-PCR, kinase inhibitors (LY294002, SB203580, PD98059), Western blot for phospho-ERK and phospho-Akt, primary human keratinocyte cultures\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple pathway inhibitors and antisense knockdowns with consistent results defining the signaling cascade\",\n      \"pmids\": [\"17274000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD8+ T cell-derived granzyme B cleaves pro-IL-18 in keratinocytes to generate mature IL-18, functioning as an alternative IL-18 converting enzyme; GrB+ /caspase-1- CD8 T cells co-cultured with IFN-γ-treated HaCaT keratinocytes transferred GrB into HaCaT cells and increased mature IL-18 in culture supernatant.\",\n      \"method\": \"CD8+ T cell and HaCaT keratinocyte co-culture, ELISA for mature IL-18, flow cytometry for GrB, PCR for caspase-1 expression\",\n      \"journal\": \"Archives of dermatological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional assay showing GrB-mediated IL-18 processing; prior reconstitution data with recombinant proteins referenced\",\n      \"pmids\": [\"23820889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-18 downregulates collagen production in human dermal fibroblasts via ERK phosphorylation and Ets-1 transcription factor; siRNA-mediated Ets-1 knockdown blocked IL-18-regulated collagen expression; ERK inhibitor PD98059 blocked IL-18's inhibitory effect; IL-18 also inhibited TGF-β-induced collagen expression and reduced collagen in SSc fibroblasts.\",\n      \"method\": \"siRNA knockdown (Ets-1), ERK inhibitor (PD98059), Western blot (phospho-ERK), RT-PCR, ELISA, primary human dermal fibroblast cultures\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — siRNA knockdown and pharmacological inhibition with mechanistic pathway placement\",\n      \"pmids\": [\"19865096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-18 induces osteopontin (OPN) expression in cardiac fibroblasts via IRF-1 transcriptional regulation; blockade of IL-18 receptor with neutralizing antibody abolished OPN expression; IRF1 mutation or siRNA reduced IL-18 and OPN expression; IRF1-mutant mice showed reduced IL-18/OPN expression and less cardiac fibrosis with pressure overload.\",\n      \"method\": \"Cardiac fibroblast culture, IL-18R neutralizing antibody, IRF1 siRNA/mutation, mouse pressure overload model, echocardiography, Western blot, RT-PCR\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — receptor blockade, siRNA, and in vivo genetic approach converge on the IL-18→IRF-1→OPN→fibrosis pathway\",\n      \"pmids\": [\"19429811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRAM (TICAM-2) acts as a sorting adaptor for MyD88 in IL-18 signaling; a direct interaction between MyD88-TIR domain and TRAM was demonstrated in vitro; TRAM-deficient mice and RNAi experiments showed reduced IL-18 signal transduction; live cell imaging showed co-localized accumulation of MyD88 and TRAM at membrane regions; TRAM binding sites on MyD88 overlap with those for Mal/TIRAP.\",\n      \"method\": \"In vitro protein interaction assay, RNAi knockdown, TRAM-deficient mice, live cell imaging (co-localization), cell-based IL-18 signaling assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding assay, KO mice, RNAi, and live imaging all supporting TRAM as IL-18 signaling adaptor\",\n      \"pmids\": [\"22685567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Inflammasomes activate caspase-1, which processes pro-IL-18 (and pro-IL-1β) to their mature active forms; NLRP3 and other NLR inflammasomes serve as the upstream activating platforms for caspase-1-dependent IL-18 maturation.\",\n      \"method\": \"Inflammasome reconstitution, caspase-1 activity assays, IL-18 maturation assays, NLR overexpression/knockout systems\",\n      \"journal\": \"Nature reviews. Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — extensive reconstitution and genetic evidence across many studies, highly cited review summarizing mechanistic data\",\n      \"pmids\": [\"23702978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The crystal structure of IL-18 bound to the ectodomain of IL-18Rα was determined; surface charge complementarity determines ligand-binding specificity of primary receptors in the IL-1 receptor family; the IL-18 signaling complex adopts an architecture similar to other agonistic IL-1 family cytokines.\",\n      \"method\": \"X-ray crystallography, structural analysis, binding site mapping\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure providing direct structural mechanism for IL-18/IL-18Rα recognition\",\n      \"pmids\": [\"25261253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The NLRP1 inflammasome is the specific inflammasome that activates IL-18 to prevent obesity and metabolic syndrome; NLRP1-deficient mice phenocopy IL-18-deficient mice with spontaneous obesity; mice with activating NLRP1 mutations have elevated IL-18, decreased adiposity, and are resistant to diet-induced metabolic dysfunction; HFD-induced fatal cachexia in NLRP1-activating mutant mice was prevented by IL-18 genetic deletion.\",\n      \"method\": \"NLRP1 and IL-18 knockout mice, NLRP1 activating-mutation knock-in mice, IL-18 ELISA, body composition analysis, high-fat/high-protein diet challenges, genetic rescue (IL-18 deletion)\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established by multiple genetic models including activating mutation rescue and IL-18 deletion reversal\",\n      \"pmids\": [\"26603191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-18 inhibits goblet cell maturation in intestinal epithelial cells by regulating the transcriptional program instructing goblet cell development; deletion of IL-18 or IL-18R1 in intestinal epithelial cells conferred protection from colitis; deletion of IL-18BP caused severe colitis with goblet cell loss that was rescued in IL-18BP-/-;IL-18rΔ/EC double mice, demonstrating the effect is mediated at the level of epithelial IL-18 signaling.\",\n      \"method\": \"Conditional epithelial cell-specific IL-18R1 and IL-18BP knockout mice, RNA-seq transcriptional analysis, histology, genetic epistasis (double knockout rescue)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic epistasis with conditional knockouts and double-KO rescue, published in Cell\",\n      \"pmids\": [\"26638073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NK cells require IL-18 signaling (via MyD88, but not IL-1R) for robust primary expansion during MCMV infection but not for memory cell maintenance or recall responses; IL-12/STAT4 signaling in activated NK cells upregulates MyD88 expression, which then mediates IL-18 downstream signaling.\",\n      \"method\": \"MCMV infection model, IL-18R-/-, MyD88-/-, IL-1R-/- mice, STAT4-/- mice, adoptive transfer, flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic knockouts establishing stage-specific requirement and signaling pathway\",\n      \"pmids\": [\"25589075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-18 promotes neonatal sepsis lethality via IL-1R1 signaling (not adaptive immunity); IL-18 increases IL-17A production by intestinal γδT cells and Ly6G+ myeloid cells; blocking IL-17A reduced IL-18-potentiated mortality, defining an IL-18→IL-1R1→IL-17A lethal axis in neonatal sepsis.\",\n      \"method\": \"IL-18-null neonatal mice, IL-1R1 KO mice, IL-18 replenishment, anti-IL-17A blockade, genome-wide mRNA analysis of human neonatal sepsis samples, flow cytometry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and antibody epistasis establishing the mechanistic pathway with both mouse and human data\",\n      \"pmids\": [\"27114524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Inflammasome-dependent activation of IL-18 (but not IL-1β) within the myocardium upon β1-AR/ROS signaling is the critical upstream regulator for chemokine expression, macrophage infiltration, and cardiac fibrosis; genetic deletion of IL-18 or NLRP3 attenuated chemokine expression and macrophage infiltration; IL-18 neutralizing antibodies selectively blocked chemokines and proinflammatory cytokines but not growth factors.\",\n      \"method\": \"Isoproterenol-induced β-AR stimulation model, IL-18 KO and NLRP3 KO mice, cytokine array, IL-18 neutralizing antibodies, cardiac histology\",\n      \"journal\": \"European heart journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and antibody approaches converging on IL-18 as specific upstream regulator in the NLRP3→IL-18→chemokine→macrophage cardiac inflammation pathway\",\n      \"pmids\": [\"28549109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-18BP is upregulated in diverse human and mouse tumors and limits IL-18 anti-tumor activity; 'decoy-resistant' IL-18 (DR-18) engineered by directed evolution is impervious to IL-18BP inhibition while maintaining signaling; DR-18 promoted poly-functional CD8+ T cells, reduced TOX+ exhausted CD8+ T cells, expanded TCF1+ stem-like CD8+ T cells, and enhanced NK cell maturation.\",\n      \"method\": \"Directed protein evolution, tumor mouse models, flow cytometry (CD8+ T cell subset analysis), IL-18BP neutralization, anti-PD-1 resistant tumor models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — engineered protein with defined mechanism plus multiple in vivo tumor models establishing IL-18BP as the key barrier to IL-18 signaling\",\n      \"pmids\": [\"32581358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Enteric neurons are the essential non-redundant source of IL-18 required for homeostatic antimicrobial protein (AMP) production by goblet cells; deletion of IL-18 specifically from enteric neurons (not immune or epithelial cells) rendered mice susceptible to invasive Salmonella infection; enteric neuronal IL-18 is specifically required for goblet cell AMP production as established by RNA-seq and single-cell sequencing.\",\n      \"method\": \"Cell type-specific conditional IL-18 knockout mice (neurons vs. immune vs. epithelial), Salmonella infection model, confocal microscopy, smFISH, RNA-seq, single-cell RNA-seq\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type specific conditional knockouts with multiple transcriptomic readouts; published in Cell\",\n      \"pmids\": [\"31923399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GSDMD activation in intestinal epithelial cells (but not immune cells) promotes IL-18 release (without affecting IL-18 transcript or maturation levels) to mediate goblet cell loss and colitis development; commensal E. coli overgrowth during colitis mediates GSDMD activation; Gsdmd-deficient mice had reduced colitis severity.\",\n      \"method\": \"DSS colitis model, Gsdmd KO mice, cell-type specific reconstitution, IL-18 ELISA (protein vs. transcript), 16S microbiome analysis, E. coli colonization experiments\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and microbiome manipulations establishing the microbiota→GSDMD→IL-18 release→goblet cell loss pathway\",\n      \"pmids\": [\"34721422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GSDMD pore structure establishes electrostatic filtering of cargo release: the GSDMD pore conduit is predominantly negatively charged, while IL-18 precursor has an acidic domain removed by caspase-1 cleavage; mature (positively charged) IL-18 passes through GSDMD pores faster than negatively charged precursor; mutation of GSDMD acidic residues compromised this selectivity.\",\n      \"method\": \"Cryo-EM structure of GSDMD pore and prepore, liposome permeabilization assay, mutagenesis, macrophage IL-18 secretion assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure plus mutagenesis plus functional liposome assay establishing electrostatic mechanism of IL-18 release through GSDMD\",\n      \"pmids\": [\"33883744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Human caspase-4 (but not mouse caspase-11) directly and efficiently processes pro-IL-18 at the same tetrapeptide site as caspase-1; the crystal structure of the caspase-4/pro-IL-18 complex reveals a binary substrate-recognition mechanism: the catalytic pocket engages the tetrapeptide, and a unique exosite (also used by caspase-1 and -5) recognizes a structure formed jointly by the propeptide and post-cleavage-site sequences; caspase-11 cannot target pro-IL-18 due to a structural deviation at the exosite; pro-IL-18 has autoinhibitory interactions between the propeptide and post-cleavage-site region; caspase cleavage induces conformational changes generating two critical IL-18Rα receptor-binding sites.\",\n      \"method\": \"Crystal structure (caspase-4/pro-IL-18 complex), in vitro cleavage assay, bacterial infection models, exosite mutagenesis (caspase-11 to restore IL-18 processing), IL-18Rα binding assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus in vitro reconstitution plus mutagenesis plus bacterial infection model in a single study\",\n      \"pmids\": [\"37993714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The GFPT2-O-GlcNAcylation-YBX1 axis promotes IL-18 secretion in pancreatic cancer cells: GFPT2-mediated O-GlcNAcylation causes YBX1 nuclear translocation, where YBX1 functions as a transcription factor to promote IL-18 transcription; confirmed by Co-IP and protein mass spectrometry identifying O-GlcNAcylated YBX1.\",\n      \"method\": \"Co-IP, protein mass spectrometry, cellular proteomics, transcription factor ChIP/reporter, YBX1 knockdown/overexpression\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP/MS and functional transcription assays in single study without independent replication\",\n      \"pmids\": [\"38575607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTBP3 promotes IL-18 exon skipping to generate a tumor-specific isoform ΔIL-18; H3K36me3 couples IL-18 transcription and alternative splicing by recruiting PTBP3 via MRG15; SETD2 (H3K36 methyltransferase) binds hnRNPL to interfere with PTBP3 binding to IL-18 pre-mRNA; ΔIL-18 promotes immune escape by reducing FBXO38-mediated PD-1 ubiquitin degradation in CD8+ T cells.\",\n      \"method\": \"mRNA-seq/GEO analysis, multi-omics, luciferase reporter for splicing, antisense oligonucleotides, HuPBMC mouse model, SETD2/PTBP3/MRG15 interaction assays, PD-1 ubiquitination assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple molecular assays in single study; novel mechanistic finding but requires independent replication\",\n      \"pmids\": [\"39116343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Caspase-3 cleavage of IL-18 in cancer cells generates a 15-kDa 'short IL-18' form that is distinct from mature IL-18: short IL-18 is not secreted and does not bind IL-18Rα; instead it translocates to the nucleus, facilitating STAT1 Ser727 phosphorylation via CDK8, and enhancing ISG15 expression and secretion; this cascade mobilizes NK cells with increased cytotoxicity to eliminate syngeneic tumors.\",\n      \"method\": \"Caspase-3 cleavage assay, subcellular fractionation, IL-18Rα binding assay, nuclear translocation imaging, CDK8 inhibition, ISG15 ELISA, syngeneic tumor models, NK cell depletion, colorectal cancer patient tissue analysis\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — novel cleavage product characterized by multiple orthogonal biochemical methods plus in vivo tumor models with mechanistic pathway (STAT1 Ser727-CDK8-ISG15-NK activation)\",\n      \"pmids\": [\"39891018\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-18 is synthesized as an inactive 24-kDa precursor constitutively present in most cells; it is processed to its active 18-kDa mature form primarily by caspase-1 within NLRP1/NLRP3/NLRC4 inflammasome complexes (and also by caspase-4/5 in a noncanonical pathway, granzyme B, and other proteases), after which GSDMD pores mediate its electrostatic-selective release; mature IL-18 signals through a heterodimeric receptor (IL-18Rα/IL-18Rβ) via MyD88 (recruited by the sorting adaptor TRAM) to activate NF-κB, AP-1, and MAPK pathways, driving IFN-γ production synergistically with IL-12 in NK and T cells, activating neutrophils, promoting DC maturation, and regulating intestinal epithelial goblet cell homeostasis; its bioactivity is tightly controlled by the high-affinity decoy receptor IL-18BP; additionally, caspase-3 generates a distinct nuclear 15-kDa short IL-18 that activates a CDK8-STAT1-ISG15-NK cell anti-tumor pathway independently of IL-18Rα.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL-18 is an IL-1 family cytokine that functions as a central orchestrator of innate and adaptive immunity, driving IFN-γ production from NK and T cells, activating neutrophils, and regulating epithelial barrier integrity and metabolic homeostasis. Synthesized as a constitutively expressed, autoinhibited 24-kDa pro-form in which the propeptide masks IL-18Rα-binding surfaces, pro-IL-18 is activated by caspase-1 (canonical inflammasome), caspase-4/5 (noncanonical inflammasome via a binary exosite recognition mechanism), and granzyme B, each cleaving the same tetrapeptide site to release the 18-kDa mature cytokine that signals through IL-18Rα/IL-18Rβ via MyD88 to activate NF-κB, AP-1, STAT1, and ERK/Akt pathways [PMID:37993714, PMID:24115947, PMID:25261253, PMID:23820889, PMID:10679398, PMID:11035116, PMID:17274000]. Mature IL-18 activity is tightly buffered by the high-affinity decoy receptor IL-18BP, whose neutralization unleashes IL-18-driven IFN-γ responses sufficient to cause macrophage activation syndrome, and whose tumor upregulation constitutes an immune checkpoint reversible by decoy-resistant IL-18 engineering [PMID:29295842, PMID:32581358]. A distinct caspase-3-generated 15-kDa nuclear form ('short IL-18') signals independently of IL-18Rα through CDK8–STAT1(Ser727)–ISG15 to mobilize NK cell anti-tumor immunity [PMID:39891018].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing that IL-18 is an IFN-γ-inducing cytokine that signals via MyD88 and activates AP-1/NF-κB resolved the fundamental question of how IL-18 drives Th1/NK cell responses and positioned it as a functional member of the IL-1 receptor signaling family.\",\n      \"evidence\": \"IL-18 knockout mice showing defective NK and Th1 responses; transcription factor assays in T cells with neutralizing antibody controls\",\n      \"pmids\": [\"10679398\", \"11035116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for IL-18Rα recognition unknown at this point\", \"Downstream signaling kinases not yet mapped\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrating that neutrophils constitutively express IL-18R and respond to IL-18 with chemokine release and respiratory burst expanded the known target cell repertoire beyond lymphocytes, and subsequent work defined a TNF-α–LTB4 axis as the mechanism of IL-18-driven neutrophil recruitment in vivo.\",\n      \"evidence\": \"Flow cytometry for receptor expression; functional assays on neutrophils; TNFRp55 knockout mice and LTB4 inhibitor epistasis\",\n      \"pmids\": [\"11509635\", \"12847274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between IL-18R engagement and LTB4 biosynthesis not resolved\", \"Whether neutrophils themselves produce IL-18 not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identifying Bcl6 as a transcriptional repressor of IL-18 via direct promoter binding revealed a mechanism controlling constitutive IL-18 expression in macrophages, with LPS relieving repression post-translationally.\",\n      \"evidence\": \"ChIP and gel retardation for Bcl6 binding; luciferase reporter assays; Bcl6 knockout macrophages\",\n      \"pmids\": [\"12817026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Post-translational modification of Bcl6 upon LPS not identified\", \"Whether Bcl6 regulation operates in non-macrophage IL-18-expressing cells unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two advances clarified pro-IL-18 biology: confirmation that pro-IL-18 is constitutively present (unlike pro-IL-1β) with its activity buffered by IL-18BP, and the demonstration that granzyme B from CTLs serves as an alternative IL-18-activating protease, broadening activation beyond inflammasome-dependent caspase-1.\",\n      \"evidence\": \"Western blot and caspase-1-deficient cell studies for precursor biology; co-culture of GrB+/caspase-1− CD8+ T cells with keratinocytes showing mature IL-18 release\",\n      \"pmids\": [\"24115947\", \"23820889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cleavage site specificity of granzyme B on pro-IL-18 not structurally resolved\", \"Relative contributions of caspase-1 vs. granzyme B in different tissues not quantified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The crystal structure of IL-18 bound to IL-18Rα ectodomain established that surface charge complementarity governs receptor selectivity, providing the structural framework for understanding how propeptide removal enables receptor engagement.\",\n      \"evidence\": \"X-ray crystallography of IL-18/IL-18Rα complex\",\n      \"pmids\": [\"25261253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ternary complex with IL-18Rβ not structurally resolved\", \"Conformational dynamics upon receptor binding not characterized\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Genetic epistasis experiments placed IL-18 downstream of NLRP1 inflammasome activation and upstream of metabolic homeostasis, while parallel work showed that epithelial IL-18 signaling controls goblet cell maturation and colitis severity, revealing tissue-specific effector functions beyond classical immunity.\",\n      \"evidence\": \"NLRP1 knockout × IL-18 knockout epistasis in obesity models; conditional IL-18/IL-18R deletion in intestinal epithelium with IL-18BP knockout rescue\",\n      \"pmids\": [\"26603191\", \"26638073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Metabolic targets of IL-18 in adipose tissue not identified\", \"Transcription factors mediating goblet cell maturation suppression not fully defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"IL-18BP-deficient mice developing macrophage activation syndrome upon TLR9 stimulation, rescuable by IL-18R or IFN-γ blockade, established that unopposed IL-18 is sufficient to drive lethal inflammatory pathology via an IL-18→IFN-γ axis, framing IL-18BP as a critical physiological brake.\",\n      \"evidence\": \"IL-18BP knockout mice; TLR9 agonist; IL-18R blocking and IFN-γ neutralizing antibodies with MAS clinical parameters\",\n      \"pmids\": [\"29295842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell types primarily producing pathogenic IFN-γ downstream of IL-18 in MAS not resolved\", \"Threshold of free IL-18 required to trigger MAS not quantified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstration that enteric neuron–derived IL-18 non-redundantly controls goblet cell antimicrobial peptide production established a neuroimmune circuit, while engineering of decoy-resistant IL-18 (DR-18) proved that IL-18BP functions as a tumor immune checkpoint by limiting anti-tumor NK and CD8+ T cell responses.\",\n      \"evidence\": \"Cell-type-specific IL-18 conditional knockouts with Salmonella infection; directed evolution of IL-18 evading IL-18BP tested in multiple mouse tumor models\",\n      \"pmids\": [\"31923399\", \"32581358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which enteric neurons sense signals to release IL-18 not defined\", \"Whether DR-18 efficacy translates to human tumors not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The crystal structure of caspase-4 bound to pro-IL-18 revealed a binary recognition mechanism — catalytic pocket engages the cleavage tetrapeptide while an exosite contacts a joint propeptide/mature-domain surface — explaining how the propeptide autoinhibits receptor binding and how cleavage induces conformational changes that expose two IL-18Rα-binding sites.\",\n      \"evidence\": \"Crystal structure of caspase-4–pro-IL-18 complex; in vitro cleavage assays and mutagenesis; confirmed for caspase-1 and caspase-5\",\n      \"pmids\": [\"37993714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of IL-18Rβ co-receptor recruitment post-cleavage not resolved\", \"Whether the exosite mechanism applies to granzyme B cleavage unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that caspase-3 generates a distinct 15-kDa nuclear 'short IL-18' that signals via CDK8–STAT1(Ser727)–ISG15 to mobilize NK cells revealed an entirely receptor-independent, intracrine signaling mode for IL-18 in cancer cells.\",\n      \"evidence\": \"In vitro caspase-3 cleavage; nuclear fractionation; CDK8 interaction; STAT1-Ser727 phosphorylation assays; syngeneic tumor models; patient colorectal cancer tissues\",\n      \"pmids\": [\"39891018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How short IL-18 is imported to the nucleus mechanistically unresolved\", \"Whether short IL-18 functions outside cancer contexts not examined\", \"Independent replication of the CDK8 interaction awaited\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structure of the full ternary IL-18/IL-18Rα/IL-18Rβ signaling complex, the precise intracellular trafficking route of short IL-18 to the nucleus, the cell-type-specific regulation of free IL-18 vs. IL-18BP balance in tissues, and whether the caspase-4/5 noncanonical pathway contributes significantly to IL-18 activation in human disease in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ternary receptor complex structure not solved\", \"Nuclear import mechanism of short IL-18 unknown\", \"In vivo quantification of free IL-18/IL-18BP ratio across tissues lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2, 5, 9, 13, 17]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5, 17, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 9, 11, 12]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 5, 9, 13, 14, 22, 24]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 17, 26, 3]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 10, 24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IL18R1\",\n      \"IL18RAP\",\n      \"IL18BP\",\n      \"CASP1\",\n      \"CASP4\",\n      \"MYD88\",\n      \"CDK8\",\n      \"GZMB\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"IL-18 is a pleiotropic pro-inflammatory cytokine of the IL-1 family that orchestrates innate and adaptive immune responses—most prominently IFN-γ production—while also regulating metabolic homeostasis, intestinal epithelial goblet cell maturation, and anti-tumor immunity. Synthesized as an inactive 24-kDa precursor constitutively present in most cell types, pro-IL-18 is processed to its mature 18-kDa form primarily by caspase-1 within NLRP1/NLRP3/NLRC4 inflammasomes, and alternatively by caspase-4/5 via an exosite-dependent mechanism or by granzyme B; the mature form is selectively released through electrostatically filtering GSDMD pores whose negative conduit charge preferentially passes the positively charged mature cytokine [PMID:8999548, PMID:37993714, PMID:33883744]. Mature IL-18 signals through the IL-18Rα/IL-18Rβ heterodimer, recruiting MyD88 via the sorting adaptor TRAM to activate NF-κB, AP-1, MAPK (ERK/PI3K-Akt), and STAT1 pathways, thereby synergizing with IL-12 to induce IFN-γ in NK cells, T cells, and B cells, activating neutrophils, promoting dendritic cell maturation, and—in enteric neurons—driving goblet cell antimicrobial peptide production [PMID:7477296, PMID:8766574, PMID:22685567, PMID:31923399, PMID:26638073]. A distinct caspase-3-generated 15-kDa nuclear 'short IL-18' activates an IL-18Rα-independent CDK8–STAT1 Ser727–ISG15 pathway that mobilizes NK cell anti-tumor cytotoxicity, while the secreted decoy receptor IL-18BP serves as the dominant negative regulator of canonical extracellular IL-18 bioactivity [PMID:39891018, PMID:32581358].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"The identification of IL-18 (IGIF) as a novel cytokine that induces IFN-γ and enhances NK cytotoxicity established its foundational role as a Th1-promoting factor distinct from IL-12.\",\n      \"evidence\": \"cDNA cloning from murine liver with recombinant protein validation in spleen cell IFN-γ induction and NK cytotoxicity assays\",\n      \"pmids\": [\"7477296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No receptor or signaling pathway identified\", \"Processing mechanism from precursor unknown\", \"Cellular sources not defined beyond liver\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstration that caspase-1 is the principal pro-IL-18 converting enzyme and that IL-18Rα (IL-1Rrp) is the cognate receptor resolved how IL-18 is activated and how it initiates signaling.\",\n      \"evidence\": \"In vitro caspase-1 cleavage assays, caspase-1 KO mice with diminished serum IL-18/IFN-γ; receptor purification from L428 cells with radioligand binding and COS-1 reconstitution\",\n      \"pmids\": [\"8999548\", \"9325300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-receptor (IL-18Rβ) not yet characterized\", \"Inflammasome platform identity unknown\", \"Mechanism of leaderless secretion unresolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"IL-18 was shown to act beyond Th1 polarization, co-inducing IL-13 with IL-2 in NK/T cells independently of IFN-γ, and its caspase-1-processed mature form was linked to Crohn's disease mucosal inflammation, broadening its functional scope.\",\n      \"evidence\": \"NK/T cell stimulation with IFN-γ KO controls for IL-13 induction; Western blot and antisense knockdown in Crohn's disease lamina propria mononuclear cells\",\n      \"pmids\": [\"10227975\", \"10384110\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Epithelial cell-intrinsic effects of IL-18 in IBD not dissected\", \"Precise Th2 vs. Th1 polarizing conditions incompletely defined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Elucidation of the IL-18Rα/IL-18Rβ heterodimer signaling through NF-κB and AP-1 via MyD88 established IL-18's signal transduction architecture and its capacity to drive IL-2 production in T cells.\",\n      \"evidence\": \"IL-18 KO mice, Jurkat cell EMSA/reporter assays, neutralizing antibody depletion of IL-18 from sarcoid fluid\",\n      \"pmids\": [\"10679398\", \"11035116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of sorting adaptors (e.g., TRAM) in MyD88 recruitment unknown\", \"Downstream transcription factor hierarchy for different cell types unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"IL-18 was shown to directly activate neutrophils and subsequently to drive neutrophil recruitment via a TNF-α→LTB4 axis, extending its function beyond lymphocyte biology to innate granulocyte responses.\",\n      \"evidence\": \"Neutrophil stimulation assays, in vivo IL-18 neutralization in carrageenan inflammation, TNFRp55 KO mice and LTB4 inhibitors\",\n      \"pmids\": [\"11509635\", \"12847274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IL-18 directly activates other granulocyte types not established\", \"Neutrophil IL-18 autocrine loops not explored\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery of polarized IL-18 secretion from dendritic cell lysosomes toward NK cells at the immunological synapse revealed a directed, non-classical release mechanism for this leaderless cytokine.\",\n      \"evidence\": \"Confocal imaging of DC–NK synapses, Ca2+ chelation and tubulin disruption, synaptic vs. non-synaptic fraction ELISA\",\n      \"pmids\": [\"15802534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of the lysosomal IL-18 loading machinery unknown\", \"Relationship to later-discovered GSDMD pore-mediated release not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapping of IL-18-activated PI3K/Akt and MEK/ERK pathways converging on NF-κB, STAT1, and IRF-1 to drive chemokine expression in keratinocytes, and the identification of granzyme B as an alternative pro-IL-18 convertase, expanded the signaling and processing repertoire.\",\n      \"evidence\": \"Kinase inhibitor panel and antisense knockdown in primary keratinocytes; CD8+ T cell/HaCaT co-culture showing GrB-dependent mature IL-18 generation\",\n      \"pmids\": [\"17274000\", \"23820889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of GrB vs. caspase-1 in vivo not quantified\", \"Cell-type specificity of PI3K/Akt vs. MAPK engagement not fully explored\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of TRAM as a sorting adaptor that directly binds MyD88-TIR to mediate IL-18 signal transduction resolved a missing link in how IL-18R engagement couples to downstream NF-κB activation.\",\n      \"evidence\": \"In vitro protein interaction assay, TRAM KO mice, RNAi knockdown, live cell co-localization imaging\",\n      \"pmids\": [\"22685567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TRAM–MyD88 interaction at the IL-18R complex not resolved\", \"Whether TRAM is required in all IL-18-responsive cell types not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Crystal structures of IL-18 bound to IL-18Rα established that electrostatic surface complementarity determines receptor specificity within the IL-1 family, providing a structural framework for understanding IL-18 signaling and decoy receptor (IL-18BP) inhibition.\",\n      \"evidence\": \"X-ray crystallography of IL-18/IL-18Rα ectodomain complex\",\n      \"pmids\": [\"25261253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full ternary complex with IL-18Rβ not structurally resolved\", \"Conformational changes upon signalosome assembly not captured\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Genetic epistasis in NLRP1 and IL-18 mutant mice established a specific NLRP1→caspase-1→IL-18 axis preventing obesity, while conditional knockout studies revealed that epithelial IL-18 signaling inhibits goblet cell maturation and that IL-18BP is a critical in vivo brake on this process.\",\n      \"evidence\": \"NLRP1 KO, activating-mutation knock-in, and IL-18 KO mice with metabolic phenotyping; conditional epithelial IL-18R1 and IL-18BP KO mice with DSS colitis and transcriptomics\",\n      \"pmids\": [\"26603191\", \"26638073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise transcriptional targets by which IL-18 suppresses goblet cell differentiation incompletely defined\", \"Whether NLRP1 vs. NLRP3 pathway dominance is tissue-specific remains unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Engineering of decoy-resistant IL-18 (DR-18) that evades IL-18BP blockade demonstrated that IL-18BP is the dominant barrier to IL-18 anti-tumor activity, and that enteric neuron-derived IL-18 is the non-redundant source for intestinal goblet cell antimicrobial defense, revealing cell-type-specific IL-18 sourcing.\",\n      \"evidence\": \"Directed evolution of DR-18 with tumor models and CD8+ T cell subset analysis; cell-type-specific conditional IL-18 KO mice (neuron, immune, epithelial) with Salmonella infection and scRNA-seq\",\n      \"pmids\": [\"32581358\", \"31923399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of IL-18 release from enteric neurons not defined\", \"DR-18 clinical translation and potential toxicities not evaluated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Cryo-EM structure of the GSDMD pore revealed that electrostatic charge filtering selectively permits passage of mature (positively charged) IL-18 over the negatively charged precursor, establishing the physical mechanism of IL-18 release.\",\n      \"evidence\": \"Cryo-EM of GSDMD pore/prepore, liposome permeabilization with charge-variant IL-18 species, GSDMD acidic-residue mutagenesis\",\n      \"pmids\": [\"33883744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo quantitative contribution of GSDMD pore vs. other release mechanisms not determined\", \"Whether GSDMD selectivity operates identically across cell types not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Crystal structure of the caspase-4/pro-IL-18 complex uncovered a binary substrate-recognition mechanism—catalytic-site tetrapeptide engagement plus a unique exosite—explaining why human caspase-4/5 but not mouse caspase-11 can process pro-IL-18, and revealed autoinhibitory intramolecular interactions in the precursor that are relieved upon cleavage to generate IL-18Rα binding sites.\",\n      \"evidence\": \"Crystal structure, in vitro cleavage reconstitution, exosite mutagenesis converting caspase-11 to gain IL-18 processing, bacterial infection models\",\n      \"pmids\": [\"37993714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the exosite mechanism operates similarly for caspase-1 in vivo not directly shown\", \"Structural basis for caspase-5 processing not independently crystallized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of tumor-specific IL-18 alternative splicing (ΔIL-18) driven by PTBP3 recruitment via H3K36me3-MRG15, with ΔIL-18 promoting immune evasion by stabilizing PD-1, and a parallel GFPT2-O-GlcNAcylation-YBX1 transcriptional axis promoting IL-18 secretion in pancreatic cancer, expanded understanding of IL-18 regulation in the tumor microenvironment.\",\n      \"evidence\": \"mRNA-seq, luciferase splicing reporters, antisense oligonucleotides, HuPBMC mouse models, Co-IP/MS for O-GlcNAcylated YBX1, ChIP for YBX1 on IL-18 promoter\",\n      \"pmids\": [\"39116343\", \"38575607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ΔIL-18 splice isoform prevalence across cancer types not established\", \"GFPT2-YBX1 axis not validated in non-pancreatic contexts\", \"Independent replication of both findings pending\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery of a caspase-3-generated nuclear 15-kDa 'short IL-18' that activates a CDK8–STAT1 Ser727–ISG15 pathway to mobilize NK cell anti-tumor cytotoxicity independently of IL-18Rα established a second, receptor-independent effector arm for IL-18.\",\n      \"evidence\": \"Caspase-3 cleavage assay, subcellular fractionation/nuclear imaging, CDK8 inhibition, ISG15 ELISA, syngeneic tumor models with NK depletion, colorectal cancer patient tissue\",\n      \"pmids\": [\"39891018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contexts beyond cancer where short IL-18 operates are unknown\", \"Whether short IL-18 nuclear translocation uses a defined import pathway not determined\", \"Structural basis for CDK8-STAT1 activation by short IL-18 not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the full ternary structure of the IL-18/IL-18Rα/IL-18Rβ signalosome, the relative quantitative contributions of different inflammasomes and caspases to IL-18 processing across tissues, the molecular mechanism of IL-18 release from enteric neurons, and the in vivo functional significance of the ΔIL-18 splice isoform.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Full ternary IL-18 signaling complex structure not solved\", \"Tissue-specific inflammasome hierarchy for IL-18 processing not quantitatively established\", \"Mechanism of IL-18 release from neurons undefined\", \"In vivo relevance of ΔIL-18 splice variant awaits independent confirmation\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 2, 5, 6, 32]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 8, 26]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [28, 32, 39]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 3, 35]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [39]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 36]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 5, 6, 8, 10, 18, 29, 32, 39]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 8, 9, 20, 24, 26]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 11, 28, 34, 38]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 25, 35, 36]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IL18R1\",\n      \"IL18RAP\",\n      \"IL18BP\",\n      \"CASP1\",\n      \"CASP4\",\n      \"GSDMD\",\n      \"MYD88\",\n      \"TICAM2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}