{"gene":"IL18","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2023,"finding":"Activated human caspase-4 (noncanonical inflammasome), but not mouse caspase-11, directly and efficiently cleaves pro-IL-18 at the same tetrapeptide site as caspase-1. Crystal structure of the caspase-4–pro-IL-18 complex revealed a binary (two-site) substrate-recognition mechanism: the catalytic pocket engages the tetrapeptide cleavage site while a unique exosite (also used by caspase-1 and caspase-5) binds a structure formed jointly by the propeptide and post-cleavage-site sequences. Pro-IL-18 harbors autoinhibitory interactions between its propeptide and post-cleavage-site region that prevent IL-18Rα binding; caspase-1/4/5 cleavage induces conformational changes generating two critical receptor-binding sites.","method":"Crystal structure of caspase-4–pro-IL-18 complex; in vitro cleavage assays; mutagenesis of exosite; bacterial infection cell models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation, in vitro reconstitution, and mutagenesis in a single rigorous study","pmids":["37993714"],"is_preprint":false},{"year":1999,"finding":"IL-18 precursor (pro-IL-18) is biologically inactive and requires cleavage by caspase-1 (ICE) to generate the active mature cytokine. The processed mature IL-18 adopts an all-beta-pleated-sheet fold similar to IL-1β.","method":"In vitro caspase-1 cleavage assay; structural comparison; functional IFN-γ induction assays","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — replicated across multiple labs, foundational biochemical processing established by in vitro assay and structural analysis","pmids":["9893178"],"is_preprint":false},{"year":1999,"finding":"IL-18 signals through a receptor complex composed of IL-18Rα (binding chain, previously identified as IL-1R-related protein/IL-1Rrp) and IL-18Rβ (signaling chain). The complex recruits IL-1R-activating kinase (IRAK) and TRAF-6, which phosphorylates NF-κB-inducing kinase leading to NF-κB activation.","method":"Receptor subunit identification; signal transduction pathway mapping by biochemical assays","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor complex components identified and signaling cascade mapped; replicated across multiple studies","pmids":["9893178"],"is_preprint":false},{"year":1998,"finding":"IL-12 upregulates expression of the IL-18 receptor on IFN-γ-producing cells, explaining the synergism between IL-12 and IL-18 in IFN-γ induction. IL-18 activates NK cells independently of IL-12.","method":"Receptor expression analysis; cytokine stimulation assays; T cell and NK cell functional assays","journal":"Current opinion in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor upregulation experiment described, synergism mechanistically explained, single review synthesizing original work","pmids":["9638361"],"is_preprint":false},{"year":2004,"finding":"In human epithelial cells stably transfected with IL-18Rβ, IL-18 signaling activates p38 MAPK (phosphorylation detectable within 5 min) rather than NF-κB; p38 MAPK inhibition reduced IL-18 activity to background. Unlike IL-1β, IL-18 did not induce IκB degradation or NF-κB reporter activation, explaining the absence of COX-2 induction and failure of IL-18 to cause fever.","method":"Stable transfection of IL-18Rβ; p38 MAPK phosphorylation assay; NF-κB reporter assay; specific kinase inhibitors; COX-2 mRNA and PGE2 measurements","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (phospho-assay, reporter assay, inhibitors, mRNA/protein measurements) in a single rigorous study","pmids":["15161979"],"is_preprint":false},{"year":2025,"finding":"In cancer cells, caspase-3 cleaves IL-18 to generate a 15-kDa 'short IL-18' form distinct from the canonical 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, facilitates STAT1 phosphorylation at Ser727 via CDK8, and enhances ISG15 expression and secretion, mobilizing NK cells with increased cytotoxicity against tumors.","method":"Caspase-3 cleavage assays; nuclear fractionation; IL-18Rα binding assays; CDK8 interaction studies; STAT1 phosphorylation analysis; syngeneic tumor models; mouse genetics","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — novel cleavage product characterized biochemically with multiple orthogonal methods and in vivo validation","pmids":["39891018"],"is_preprint":false},{"year":2003,"finding":"Bcl6 is a transcriptional repressor of IL-18. Bcl6-binding DNA sequences (IL-18BS) were identified upstream of exon 1 of murine IL-18 and in the promoter of human IL-18. Bcl6 binding to IL-18BS in resting macrophages was demonstrated by gel retardation and chromatin immunoprecipitation; binding diminished after LPS stimulation despite constant Bcl6 protein levels, indicating functional modification of Bcl6 post-stimulation. IL-18BS was required for Bcl6-mediated repression of an IL-18 promoter-luciferase reporter.","method":"Gel retardation (EMSA); chromatin immunoprecipitation (ChIP); luciferase reporter assay; dominant-negative Bcl6 transfection; Bcl6-/- macrophages","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (EMSA, ChIP, reporter assay, KO cells) in a single study","pmids":["12817026"],"is_preprint":false},{"year":2017,"finding":"Type I IFN (IFNα/β) signaling is essential for IL-18 induction in macrophages: macrophages lacking type I IFN signaling are impaired in IL-18 induction after TLR stimulation. IL-18 expression is sustained after chronic TLR stimulation (escaping endotoxin tolerance) while IL-1β is not, revealing a fundamental regulatory difference.","method":"TLR stimulation of macrophages; IFN signaling-deficient macrophages; cytokine mRNA and protein measurement; chronic vs. acute TLR stimulation","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO/deficient-cell experiments with defined phenotypic readout, single lab, two orthogonal approaches","pmids":["28468974"],"is_preprint":false},{"year":2020,"finding":"IL-18 production from human monocytes requires cooperative TLR and IFNα/β signaling; JAK/STAT inhibition or IFNβ neutralization during LPS stimulation blunted IL-18 expression. This mechanism was confirmed in two MAS mouse models and a patient, where JAK/STAT inhibition reduced IL-18 serum levels. IL-18 (but not IL-1β) expression escapes LPS-induced immunoparalysis.","method":"Primary human monocyte stimulation; JAK/STAT inhibitors; IFNβ neutralization; MAS mouse models; patient serum analysis","journal":"American journal of respiratory and critical care medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition and neutralization experiments in vitro and in vivo, translated to patient data","pmids":["31710506"],"is_preprint":false},{"year":2015,"finding":"IL-18 signaling in intestinal epithelial cells (IECs) drives colitis and inhibits goblet cell maturation by regulating the transcriptional program instructing goblet cell development. Deletion of Il18 or Il18r1 specifically in IECs protected mice from colitis; deletion of IL-18 negative regulator Il18bp caused severe colitis with goblet cell loss, which was rescued in Il18bp−/−;Il18r(ΔEC) mice, placing colitis severity at the level of IL-18 signaling in IECs.","method":"Conditional knockout mice (Il18 ΔEC, Il18r1 ΔEC, Il18bp−/−); double-mutant epistasis; goblet cell transcriptional program analysis; DSS colitis model","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with genetic epistasis rescue experiment defining pathway position, published in Cell","pmids":["26638073"],"is_preprint":false},{"year":2020,"finding":"Enteric neurons (not immune or epithelial cells) are a source of IL-18 and this neuronal IL-18 is specifically required for homeostatic goblet cell antimicrobial protein (AMP) production. Deletion of IL-18 from enteric neurons alone rendered mice susceptible to invasive Salmonella typhimurium infection.","method":"Cell-type-specific Il18 deletion; smFISH for IL-18 mRNA in neurons; RNA-seq and single-cell sequencing; bacterial infection model","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO with defined functional phenotype and RNA-seq mechanistic follow-up","pmids":["31923399"],"is_preprint":false},{"year":2015,"finding":"NLRP1 inflammasome activation is the upstream regulator that produces IL-18 to prevent obesity and metabolic syndrome. Mice lacking NLRP1 phenocopy IL-18-deficient mice (spontaneous obesity, lipid accumulation); mice with an activating NLRP1 mutation and elevated IL-18 are resistant to diet-induced obesity; fatal cachexia in these mice on high-fat diet is prevented by genetic IL-18 deletion, placing IL-18 downstream of NLRP1.","method":"NLRP1 KO and activating-mutation knock-in mice; IL-18 KO rescue; high-fat diet metabolic phenotyping; genetic epistasis","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic epistasis with multiple KO and knock-in lines, metabolic phenotype clearly defined","pmids":["26603191"],"is_preprint":false},{"year":2001,"finding":"Human peripheral blood neutrophils constitutively express IL-18Rα and IL-18Rβ and respond directly to IL-18 by releasing cytokines/chemokines (protein-synthesis dependent), upregulating CD11b, inducing granule release, and enhancing respiratory burst. IL-18 administration in vivo promoted neutrophil accumulation; IL-18 neutralization suppressed carrageenan-induced footpad inflammation and reduced tissue MPO and TNF-α.","method":"Flow cytometry for IL-18R expression; IL-18 stimulation of isolated neutrophils; protein synthesis inhibitor controls; in vivo carrageenan inflammation model; IL-18 neutralizing antibody","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor expression plus functional in vitro and in vivo experiments in a single study","pmids":["11509635"],"is_preprint":false},{"year":2003,"finding":"IL-18 promotes neutrophil accumulation in vivo via a TNF-α → leukotriene B4 (LTB4) cascade: IL-18-induced neutrophil recruitment and LTB4 production were blocked by anti-TNF-α antibody or absence of TNFRp55, and by the LTB4 synthesis inhibitor MK-886 or LTB4 receptor antagonist. Human neutrophils activated by IL-18 also produced LTB4.","method":"Peritoneal neutrophil recruitment assay; TNFRp55-/- mice; LTB4 inhibitor MK-886; LTB4 receptor antagonist; anti-TNF-α neutralization; IL-18-dependent collagen-induced arthritis model","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological dissection of pathway in vivo and in vitro, single lab","pmids":["12847274"],"is_preprint":false},{"year":2006,"finding":"IL-18 bridges innate and adaptive immunity independently of IL-12 by inducing OX40L on dendritic cells; peptide stimulation induces CD134 (OX40) on antigen-specific T cells. CD134 blockade inhibited T cell effector expansion and reduced IFN-γ super-producers by 12-fold. The effect required host-derived IFN-γ but not NK cells or IL-12.","method":"In vivo mouse immunization; CD134 blockade; IFN-γ−/− mice; NK cell depletion; IL-12 blockade; T cell clonal expansion assays","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and antibody-blockade epistasis in vivo, multiple controls, single lab","pmids":["16785519"],"is_preprint":false},{"year":2013,"finding":"IL-18 and IL-1β are independently regulated downstream of NLRP3 inflammasome activation: ROS production (via caspase-11) is required for IL-1β secretion but not IL-18 secretion. Caspase-11-deficient DCs failed to secrete IL-1β in response to Listeria p60 but retained full IL-18 secretion.","method":"NLRP3 inflammasome activation with Listeria p60; ROS inhibitors; caspase-11-deficient DCs; ELISA for IL-1β and IL-18","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO and pharmacological dissection showing independent licensing, single lab","pmids":["23028835"],"is_preprint":false},{"year":2012,"finding":"In IL-18-deficient mice with CAPS-associated NLRP3 mutations, IL-18 receptor deletion provided greater phenotypic rescue (abolished skin and visceral disease, normalized serum cytokines) than IL-1R deletion at early stages, demonstrating distinct roles for IL-18 vs. IL-1β in CAPS pathology. Persistent inflammation in double-cytokine receptor KO CAPS mice implicated caspase-1-mediated pyroptosis as an additional pathway.","method":"CAPS mouse models bred onto Il18r-null and Il1r-null backgrounds; phenotypic and cytokine analyses; genetic epistasis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous genetic epistasis with multiple KO combinations, clear phenotypic rescue hierarchy established","pmids":["24084736"],"is_preprint":false},{"year":2001,"finding":"IL-18BP is a high-affinity naturally occurring binding protein that neutralizes IL-18 in the fluid phase, balancing its biological activity. Human IL-18BP and orthopoxvirus homologs bind both human and murine IL-18 with measurable dissociation constants (viral proteins show 12–50-fold lower Kd for murine vs. human IL-18); binding inhibits IFN-γ induction by IL-18.","method":"Surface plasmon resonance (SPR/Biacore) affinity measurements; IFN-γ induction bioassay inhibition","journal":"Virology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — SPR quantitative binding measurements plus functional bioassay, rigorous biophysical method","pmids":["11145885"],"is_preprint":false},{"year":2018,"finding":"Inflammasome-dependent IL-18 (not IL-1β) is the critical upstream regulator of chemokine expression and macrophage infiltration in the myocardium upon acute β1-AR/ROS signaling by isoproterenol. Genetic deletion of IL-18 or NLRP3 significantly attenuated chemokine expression and macrophage infiltration. IL-18 neutralizing antibodies selectively abated proinflammatory cytokines but not growth factors, and early IL-18 blockade prevented cardiac fibrosis.","method":"Cytokine array; IL-18−/− and NLRP3−/− mice; IL-18 neutralizing antibodies; isoproterenol model; histology for fibrosis and macrophage infiltration","journal":"European heart journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and antibody blockade with defined cellular phenotype, single lab","pmids":["28549109"],"is_preprint":false},{"year":2009,"finding":"IL-18 induces osteopontin (OPN) expression in cardiac fibroblasts via IRF1 transcription factor, leading to interstitial fibrosis and diastolic dysfunction. Blockade of the IL-18 receptor abolished conditioned-medium-induced OPN upregulation; IRF1 mutation or siRNA reduced IL-18 and OPN in cardiac fibroblasts; IRF1-mutant mice showed downregulated IL-18/OPN and reduced fibrosis under pressure overload.","method":"Recombinant IL-18 treatment of cardiac fibroblasts; IL-18R neutralizing antibody; IRF1 siRNA knockdown; IRF1-mutant mice; pressure/volume overload models; Western blot/qPCR","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor blockade, siRNA, and KO mouse converging on same mechanism, single lab","pmids":["19429811"],"is_preprint":false},{"year":2013,"finding":"IL-18 induces profibrotic changes in renal tubular epithelial cells (HK-2) via STAT3 activation: IL-18 increased phospho-STAT3, SOCS3, α-SMA, collagen III expression and TEC apoptosis in vitro, effects significantly diminished by the STAT3 inhibitor S3I-201. In vivo, IL-18 neutralization (via IL-18BP transgene) reduced p-STAT3 after ureteral obstruction.","method":"IL-18 stimulation of HK-2 cells; STAT3 inhibitor S3I-201; Western blotting for p-STAT3; IL-18BP transgenic mice with ureteral obstruction","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro pharmacological inhibition plus in vivo transgenic confirmation, single lab","pmids":["23904224"],"is_preprint":false},{"year":2009,"finding":"IL-18 downregulates type I and III collagen production in human dermal fibroblasts through Ets-1 transcription factor and ERK pathway activation: ERK phosphorylation occurred within 10 min of IL-18 treatment; ERK inhibitor PD98059 blocked IL-18's inhibitory effect on collagen; Ets-1 siRNA knockdown abolished IL-18-regulated collagen suppression.","method":"ERK phosphorylation assay; PD98059 ERK inhibitor; Ets-1 siRNA; collagen gene expression and protein measurement; primary dermal fibroblast and SSc fibroblast cultures","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA and pharmacological inhibitor converging on Ets-1/ERK pathway, single lab","pmids":["19865096"],"is_preprint":false},{"year":2006,"finding":"IL-18 acts synergistically with IL-15 to stimulate NK cell proliferation in vitro through direct stimulation of NK cells rather than via an intermediary cell type (shown using an NK cell line).","method":"In vitro NK cell proliferation assay; NK cell line (excluding indirect signaling); IL-18 + IL-15 co-stimulation","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean in vitro demonstration with cell-line control excluding indirect mechanism, single lab single method","pmids":["17052916"],"is_preprint":false},{"year":2017,"finding":"IL-18 drives ILC3 proliferation and IL-22 production via NF-κB: the p65 NF-κB subunit binds the proximal IL22 promoter and promotes transcriptional activity downstream of IL-18 signaling. CD11c+ dendritic cells expressing IL-18 were found adjacent to ILC3s in human tonsils in situ.","method":"IL-18 stimulation of human ILC3s; NF-κB pathway analysis; p65 promoter binding (ChIP/reporter); in situ human tonsil immunostaining","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter binding and NF-κB pathway mechanistic experiments plus in situ tissue validation, single lab","pmids":["28842466"],"is_preprint":false},{"year":2013,"finding":"CD8+ T cell-derived granzyme B cleaves keratinocyte pro-IL-18 into its active form; co-culture of granzyme B+/caspase-1− CD8+ T cells with IFN-γ-treated HaCaT keratinocytes resulted in GrB transfer into keratinocytes and increased mature IL-18 in culture supernatant.","method":"CD8+ T cell/HaCaT keratinocyte co-culture; flow cytometry for intracellular GrB; ELISA for mature IL-18; GrB+/caspase-1− T cell validation by PCR","journal":"Archives of dermatological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-culture experiment with protein transfer and mature IL-18 measurement, single lab","pmids":["23820889"],"is_preprint":false},{"year":2001,"finding":"IFN-γ induces expression and secretion of IL-18 binding protein (IL-18BPa) from human colon carcinoma/epithelial cells (DLD-1, LoVo, Caco-2, HCT116) and keratinocytes (HaCaT); secreted IL-18BPa significantly impaired IL-18/IL-12-stimulated IFN-γ release from PBMC. Sodium butyrate suppressed IFN-γ-induced IL-18BPa but not IL-18 expression, suggesting context-dependent modulation.","method":"IFN-γ stimulation; IL-18BPa mRNA and protein measurement; functional IFN-γ production bioassay; sodium butyrate treatment; organ cultures from intestinal biopsies","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — induction and functional neutralization demonstrated in multiple cell lines plus ex vivo tissue, single lab","pmids":["11739524"],"is_preprint":false},{"year":2024,"finding":"In pancreatic cancer cells, GFPT2-mediated O-GlcNAcylation promotes nuclear translocation of YBX1, which then functions as a transcription factor to promote IL-18 transcription, linking HBP metabolism to IL-18-dependent immune microenvironment regulation.","method":"Co-IP; protein mass spectrometry identifying YBX1 O-GlcNAcylation; transcriptional reporter assays; GFPT2 KO/knockdown; cellular proteomics","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and MS identification of modification plus functional transcriptional assay, single lab","pmids":["38575607"],"is_preprint":false},{"year":2024,"finding":"IL-18 stimulation activates SLC12A3 (NCC) in macrophages, leading to sodium influx, mitochondrial DNA release, and STING activation, reprogramming macrophages from glycolysis to fatty acid oxidation (FAO). This metabolic switch is maintained by a bistable feedback loop involving macrophage-derived 2'3'-cGAMP and epithelial IL-18, encoding durable intestinal immune tolerance.","method":"Metabolic flux analysis; SLC12A3 inhibition/KO; STING KO; mitochondrial DNA measurement; cGAMP measurement; intestinal tolerance models","journal":"Immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic and pharmacological perturbations establishing pathway order, single lab, complex in vivo system","pmids":["38906145"],"is_preprint":false},{"year":2011,"finding":"IL-18 produced by tumor cells promotes the development of NK-cell-controlled metastases in a PD-1-dependent manner; IL-18 upregulates PD-1 on mature NK cells in lymphoid organs of tumor-bearing mice. RNAi knockdown of IL-18 in tumors or systemic depletion by IL-18BP stimulated NK cell-dependent immunosurveillance.","method":"Tumor-derived IL-18 knockdown (RNAi); IL-18BP depletion; PD-1 expression analysis on NK cells; PD-1-deficient mice; metastasis models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi and neutralization approaches with KO mice establishing PD-1 dependence, single lab","pmids":["21724589"],"is_preprint":false},{"year":2020,"finding":"IL-18BP is frequently upregulated in tumors and limits IL-18 anti-tumor activity. A directed-evolution-engineered 'decoy-resistant' IL-18 (DR-18) maintains IL-18R signaling but is impervious to IL-18BP inhibition; DR-18 promoted poly-functional effector CD8+ T cells, reduced TOX+ exhausted CD8+ T cells, expanded TCF1+ stem-like CD8+ T cells, and enhanced NK cell activity in anti-PD-1-resistant tumors lacking MHC-I.","method":"Directed evolution; IL-18BP binding assays; mouse tumor models; flow cytometry for T cell subsets; comparison with wild-type IL-18","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — engineered variant with mechanistic binding characterization, multiple in vivo tumor models, and defined immune cell phenotypes","pmids":["32581358"],"is_preprint":false},{"year":2016,"finding":"IL-18-mediated lethality in neonatal sepsis requires IL-1R1 signaling (not adaptive immunity) and depends on IL-17A produced by intestinal γδT cells and Ly6G+ myeloid cells. IL-18 administration increased IL-17A production, and blocking IL-17A reduced IL-18-potentiated mortality in both neonatal sepsis and endotoxemia, placing IL-17A as an effector downstream of IL-18.","method":"IL-18−/− neonatal mice; IL-1R1 KO; γδT cell analysis; IL-17A blockade; genome-wide blood mRNA analysis from septic neonates","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and cytokine blockade defining pathway order in vivo, single lab","pmids":["27114524"],"is_preprint":false},{"year":2007,"finding":"IL-18 is constitutively expressed specifically in the intercalated cells of the late distal convoluted tubule, connecting tubule, and collecting duct of the healthy human kidney. These same cells also express caspase-1 and P2X7 receptor (both required for IL-18 processing and secretion), establishing the cellular machinery for IL-18 activation at this site.","method":"In situ hybridization; immunohistochemistry with cell-type markers (calbindin-D28k, aquaporin-2, vacuolar H+-ATPase); confocal microscopy; Western blot; PCR","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal localization methods with co-localization of processing machinery, single lab","pmids":["17687255"],"is_preprint":false},{"year":2006,"finding":"IL-18 reduces UV-induced DNA damage in keratinocytes and prevents photoimmunosuppression via promotion of DNA repair; the effect was absent in Xpa-knockout (DNA repair-deficient) mice, demonstrating dependence on nucleotide excision repair. Unlike IL-12, IL-18 did not break UV-induced immunotolerance mediated by regulatory T cells.","method":"UV irradiation of mice; IL-18 injection; apoptosis and DNA damage immunohistochemistry; Xpa-KO mice; contact hypersensitivity readout","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO (Xpa) establishing DNA repair dependence, in vivo functional assay, single lab","pmids":["16493047"],"is_preprint":false},{"year":2018,"finding":"IL-18 reduces voltage-gated potassium channel (Ito current) expression in cardiomyocytes, causing electrical remodeling and ventricular tachycardia. Sustained IL-18 inhibition with IL-18BP in SCD mice decreased cardiac fibrosis, NF-κB phosphorylation, improved diastolic function, and attenuated VT; recombinant IL-18 administered to isolated hearts triggered VT from the right ventricle.","method":"SCD humanized mouse model; IL-18BP treatment; patch-clamp recording of Ito; recombinant IL-18 in isolated hearts; NF-κB phosphorylation assay; echocardiography","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ex vivo IL-18 administration plus in vivo inhibition with defined electrophysiological readout, single lab","pmids":["33181835"],"is_preprint":false},{"year":2006,"finding":"IL-18 enhances thrombospondin-1 (TSP-1) production in human gastric cancer cells in a dose- and time-dependent manner via JNK pathway activation: SP600125 (JNK inhibitor) blocked IL-18-enhanced TSP-1 expression; IL-18 increased phosphorylated JNK as detected by Western blot.","method":"RT-PCR; ELISA; JNK inhibitor SP600125; phospho-JNK Western blot","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological inhibitor with signaling readout, single lab, single cytokine pathway","pmids":["16650813"],"is_preprint":false},{"year":2018,"finding":"Unopposed IL-18 signaling (in IL-18BP-deficient mice) drives severe MAS upon TLR9 stimulation, with IL-18 acting upstream of IFN-γ. Blocking IL-18 receptor signaling attenuated MAS severity and IFN-γ responses; blocking IFN-γ had comparable effects, establishing the IL-18→IFN-γ axis in MAS pathogenesis.","method":"IL-18BP-KO mice; TLR9/CpG stimulation; IL-18R blockade; IFN-γ blockade; serum cytokine and IFN-γ signature gene analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus antibody blockade epistasis in vivo, single lab","pmids":["29295842"],"is_preprint":false},{"year":2002,"finding":"Langerhans cell-derived IL-18, processed by caspase-1, contributes to contact hypersensitivity initiation: caspase-1−/− mice had impaired IFN-γ production from LN cells that was restored by exogenous IL-18; CHS responses were inhibited by anti-IL-18 antibody and in caspase-1−/− mice; migratory hapten-modified LC in LN expressed high IL-18 mRNA and secreted functional IL-18.","method":"Caspase-1-KO mice; exogenous IL-18 rescue; anti-IL-18 neutralizing antibody; CHS in vivo model; mRNA expression in LN cells","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with exogenous rescue plus antibody blockade, single lab","pmids":["11907086"],"is_preprint":false},{"year":2019,"finding":"Choline uptake via CTL1 transporter in macrophages supports NLRP3 inflammasome activation and IL-18 production; inhibition of CTL1 or choline kinase altered mitochondrial lipid profile, attenuated mitochondrial ATP synthesis, and activated AMPK, which stimulates DRP1-mediated mitophagy to terminate NLRP3 inflammasome activation.","method":"CTL1 inhibition/knockdown; choline kinase inhibitors; mitochondrial lipid profiling; AMPK activation assay; DRP1 mitochondrial recruitment; mitophagy assay; IL-18 ELISA","journal":"Cell metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays defining metabolic pathway upstream of IL-18, single lab","pmids":["30982734"],"is_preprint":false}],"current_model":"IL-18 is synthesized as an inactive precursor constitutively present in most cells; it is cleaved into its active 18-kDa mature form primarily by caspase-1 (canonical inflammasome) and also by caspase-4/5 (noncanonical inflammasome) at the same tetrapeptide site via a binary recognition mechanism (catalytic pocket plus exosite), or by extracellular proteases such as granzyme B; caspase-3 generates a distinct 15-kDa nuclear 'short IL-18' that does not bind IL-18Rα but instead activates CDK8-STAT1-ISG15 signaling to mobilize NK cells. Mature IL-18 signals through a heterodimeric receptor (IL-18Rα/IL-18Rβ), primarily via p38 MAPK (and secondarily NF-κB in some contexts), to drive IFN-γ production from T and NK cells (synergistically with IL-12, which upregulates IL-18R), neutrophil activation via TNF-α/LTB4, ILC3 IL-22 production via NF-κB/p65, and OX40L induction on dendritic cells. Its activity is tightly neutralized by the high-affinity soluble decoy IL-18BP, which is induced by IFN-γ and IL-27. Transcriptionally, IL-18 expression is constitutively driven and repressed by Bcl6 (which binds an IL-18BS element in the promoter), and its induction requires cooperative TLR and type I IFN/JAK-STAT signaling that escapes endotoxin tolerance."},"narrative":{"mechanistic_narrative":"IL-18 is a constitutively expressed proinflammatory cytokine of the IL-1 family that bridges innate and adaptive immunity, acting as a central upstream driver of IFN-γ responses, tissue homeostasis, and inflammatory pathology [PMID:9893178, PMID:26638073]. It is synthesized as an inactive precursor whose propeptide and post-cleavage-site sequences engage in autoinhibitory interactions that occlude IL-18Rα binding; proteolytic maturation relieves this autoinhibition and generates two receptor-binding surfaces [PMID:37993714]. Canonical activation is performed by caspase-1, which cleaves pro-IL-18 to the active 18-kDa cytokine [PMID:9893178], while the human noncanonical inflammasome caspase-4 (but not mouse caspase-11) cleaves at the identical tetrapeptide site through a binary mechanism combining the catalytic pocket with an exosite shared by caspase-1/4/5 [PMID:37993714]; extracellular maturation is achieved by CD8+ T-cell granzyme B transferred into target cells [PMID:23820889]. Mature IL-18 signals through the heterodimeric IL-18Rα/IL-18Rβ receptor, recruiting IRAK and TRAF6 [PMID:9893178] and signaling predominantly via p38 MAPK rather than NF-κB, a feature that distinguishes it from IL-1β and explains its failure to induce COX-2 or fever [PMID:15161979]. Receptor engagement drives IFN-γ production synergistically with IL-12 (which upregulates the IL-18 receptor) [PMID:9638361], NK-cell proliferation and activity [PMID:17052916], ILC3 IL-22 production via NF-κB p65 [PMID:28842466], OX40L-dependent T-cell priming [PMID:16785519], and direct neutrophil activation through a TNF-α→LTB4 cascade [PMID:11509635, PMID:12847274]. IL-18 activity is governed transcriptionally by Bcl6 repression at an IL-18BS promoter element [PMID:12817026] and by cooperative TLR plus type I IFN/JAK-STAT signaling that allows IL-18 to escape endotoxin tolerance [PMID:28468974, PMID:31710506], and post-translationally by the high-affinity soluble decoy IL-18BP, which is induced by IFN-γ [PMID:11145885, PMID:11739524]. Genetic epistasis places IL-18 downstream of the NLRP1 and NLRP3 inflammasomes in metabolic and autoinflammatory disease, including macrophage activation syndrome via an IL-18→IFN-γ axis [PMID:26603191, PMID:24084736, PMID:29295842], and at the epithelial interface IL-18 controls goblet-cell programs, antimicrobial defense, and intestinal tolerance [PMID:26638073, PMID:31923399, PMID:38906145]. A distinct caspase-3–generated 15-kDa 'short IL-18' does not bind IL-18Rα but translocates to the nucleus to drive CDK8-dependent STAT1 Ser727 phosphorylation and ISG15 expression, mobilizing antitumor NK cells [PMID:39891018]. Engineered decoy-resistant IL-18 that evades IL-18BP enhances stem-like CD8+ T-cell and NK-cell antitumor immunity, defining IL-18BP as a key brake on its therapeutic activity [PMID:32581358].","teleology":[{"year":1998,"claim":"Establishing why IL-12 and IL-18 synergize for IFN-γ answered how two distinct cytokines cooperate, showing IL-12 upregulates the IL-18 receptor on IFN-γ-producing cells while IL-18 can activate NK cells independently.","evidence":"Receptor expression analysis and T/NK cell functional assays","pmids":["9638361"],"confidence":"Medium","gaps":["Synthesized within a review rather than a single primary dataset","Does not define the receptor signaling branch driving IFN-γ"]},{"year":1999,"claim":"Defining pro-IL-18 maturation and the receptor complex established the core activation logic: caspase-1 cleavage of an inactive precursor yields an IL-1β-like cytokine that signals through IL-18Rα/IL-18Rβ via IRAK/TRAF6 to NF-κB.","evidence":"In vitro caspase-1 cleavage, structural comparison, receptor subunit identification, and signal-transduction mapping","pmids":["9893178"],"confidence":"High","gaps":["Did not resolve the structural basis of propeptide autoinhibition","NF-κB assignment later refined to p38 MAPK in epithelial contexts"]},{"year":2001,"claim":"Quantifying IL-18BP binding defined the principal extracellular brake on IL-18, showing high-affinity neutralization of both human and murine IL-18 by host and viral decoy proteins.","evidence":"Surface plasmon resonance affinity measurements with IFN-γ induction bioassay","pmids":["11145885"],"confidence":"High","gaps":["Did not address in vivo regulation of IL-18BP abundance","Structural basis of the IL-18:IL-18BP interface not resolved"]},{"year":2001,"claim":"Identifying IFN-γ-induced IL-18BP from epithelial cells defined a negative feedback loop, linking IL-18-driven IFN-γ to its own neutralization.","evidence":"IFN-γ stimulation with IL-18BPa measurement and IFN-γ production bioassays in cell lines and intestinal organ cultures","pmids":["11739524"],"confidence":"Medium","gaps":["Did not establish the in vivo physiological consequence of the feedback","Mechanism of butyrate modulation undefined"]},{"year":2001,"claim":"Demonstrating direct neutrophil responsiveness answered whether IL-18 acts on innate effectors directly, showing constitutive IL-18R expression and functional activation of neutrophils plus a role in acute inflammation.","evidence":"Flow cytometry, neutrophil stimulation with synthesis-inhibitor controls, and in vivo carrageenan model with IL-18 neutralization","pmids":["11509635"],"confidence":"Medium","gaps":["Did not define downstream signaling in neutrophils","Effector mediators of recruitment unresolved until later work"]},{"year":2002,"claim":"Showing Langerhans-cell IL-18 drives contact hypersensitivity established caspase-1-processed IL-18 as an initiator of cutaneous adaptive immunity.","evidence":"Caspase-1-KO mice with exogenous IL-18 rescue and anti-IL-18 neutralization in a CHS model","pmids":["11907086"],"confidence":"Medium","gaps":["Did not define the receptor signaling branch in this setting","Cellular target of IL-18 in the lymph node not pinpointed"]},{"year":2003,"claim":"Identifying Bcl6 as a promoter repressor answered how constitutive IL-18 transcription is restrained, showing LPS-induced loss of Bcl6 occupancy at the IL-18BS element derepresses the gene.","evidence":"EMSA, ChIP, luciferase reporter, dominant-negative Bcl6, and Bcl6-/- macrophages","pmids":["12817026"],"confidence":"High","gaps":["Post-stimulation modification of Bcl6 not molecularly defined","Did not connect to type I IFN co-regulation later identified"]},{"year":2003,"claim":"Dissecting the TNF-α→LTB4 cascade defined the mechanism by which IL-18 recruits neutrophils, ordering soluble mediators downstream of receptor engagement.","evidence":"TNFRp55-/- mice, anti-TNF-α, LTB4 synthesis/receptor antagonists in peritoneal recruitment and arthritis models","pmids":["12847274"],"confidence":"Medium","gaps":["Cell source of TNF-α in the cascade not pinned","Intracellular signaling linking IL-18R to LTB4 synthesis undefined"]},{"year":2004,"claim":"Resolving the dominant signaling branch reconciled IL-18's non-pyrogenic phenotype, showing rapid p38 MAPK activation without IκB degradation or NF-κB reporter activity, unlike IL-1β.","evidence":"Stable IL-18Rβ transfection, phospho-p38 assay, NF-κB reporter, kinase inhibitors, COX-2/PGE2 measurement","pmids":["15161979"],"confidence":"High","gaps":["Context dependence of NF-κB vs p38 across cell types not resolved","Used a transfected epithelial system"]},{"year":2006,"claim":"Defining the OX40L/CD134 axis showed how IL-18 links innate signals to T-cell expansion independently of IL-12 and NK cells, while requiring host IFN-γ.","evidence":"In vivo immunization with CD134 blockade, IFN-γ-/- mice, NK depletion, and IL-12 blockade","pmids":["16785519"],"confidence":"Medium","gaps":["Direct vs indirect induction of dendritic-cell OX40L not separated","Receptor signaling pathway in this context unmapped"]},{"year":2006,"claim":"Showing direct IL-15 synergy on an NK cell line established that IL-18-driven NK proliferation is cell-intrinsic rather than mediated by an intermediary cell.","evidence":"In vitro NK cell-line proliferation with IL-18 + IL-15 co-stimulation","pmids":["17052916"],"confidence":"Medium","gaps":["Single in vitro method","Molecular basis of IL-18/IL-15 synergy undefined"]},{"year":2006,"claim":"Linking IL-18 to UV-induced DNA repair showed a protective, repair-dependent role in keratinocytes distinct from immunosuppressive cytokines.","evidence":"UV irradiation of mice with IL-18 injection and Xpa-KO repair-deficient mice with contact hypersensitivity readout","pmids":["16493047"],"confidence":"Medium","gaps":["Molecular link between IL-18 signaling and nucleotide excision repair unresolved","Receptor dependence not directly tested"]},{"year":2009,"claim":"Identifying divergent fibroblast responses showed IL-18 can be pro- or anti-fibrotic depending on tissue, acting via IRF1-osteopontin in cardiac fibroblasts versus Ets-1/ERK suppression of collagen in dermal fibroblasts.","evidence":"IL-18 stimulation with receptor blockade, IRF1 siRNA/mutant mice and Ets-1 siRNA/ERK inhibition in fibroblast cultures and overload models","pmids":["19429811","19865096"],"confidence":"Medium","gaps":["Determinants of opposing fibroblast responses across tissues unexplained","Single-lab mechanisms per tissue"]},{"year":2011,"claim":"Revealing tumor-derived IL-18 induces NK-cell PD-1 uncovered an immunosuppressive arm of IL-18 that promotes metastasis, complicating its antitumor role.","evidence":"Tumor IL-18 RNAi, IL-18BP depletion, NK PD-1 analysis, and PD-1-deficient mice in metastasis models","pmids":["21724589"],"confidence":"Medium","gaps":["Mechanism of PD-1 upregulation by IL-18 undefined","Context distinguishing pro- vs antitumor IL-18 not resolved"]},{"year":2012,"claim":"Genetic epistasis in CAPS established distinct, non-redundant roles for IL-18 and IL-1β, with IL-18R deletion providing greater early rescue and implicating pyroptosis in residual disease.","evidence":"CAPS mice on Il18r-null and Il1r-null backgrounds with phenotypic and cytokine analyses","pmids":["24084736"],"confidence":"High","gaps":["Cellular source of pathogenic IL-18 in CAPS not defined","Residual pyroptotic pathway not molecularly dissected"]},{"year":2013,"claim":"Defining inflammasome heterogeneity showed IL-18 and IL-1β secretion are independently licensed downstream of NLRP3, with ROS/caspase-11 required for IL-1β but not IL-18.","evidence":"Listeria p60 NLRP3 activation, ROS inhibitors, caspase-11-deficient DCs and ELISA","pmids":["23028835"],"confidence":"Medium","gaps":["Molecular basis of differential licensing unresolved","Single stimulus/cell type"]},{"year":2013,"claim":"Identifying granzyme B as an extracellular protease that matures pro-IL-18 showed inflammasome-independent activation, with CD8+ T cells processing keratinocyte IL-18.","evidence":"CD8+ T cell/HaCaT co-culture with intracellular GrB tracking and mature IL-18 ELISA","pmids":["23820889"],"confidence":"Medium","gaps":["Cleavage site for granzyme B not mapped","In vivo relevance not established"]},{"year":2013,"claim":"Defining IL-18→STAT3 in renal tubular cells established a profibrotic signaling route in kidney injury distinct from the p38 axis.","evidence":"IL-18 stimulation of HK-2 cells with STAT3 inhibitor and IL-18BP transgenic mice in ureteral obstruction","pmids":["23904224"],"confidence":"Medium","gaps":["Link between IL-18R and STAT3 activation undefined","Single lab"]},{"year":2015,"claim":"Conditional knockouts placed IL-18 signaling within intestinal epithelial cells as a driver of colitis and a repressor of goblet-cell maturation, with IL-18BP loss causing severe disease rescued by epithelial receptor deletion.","evidence":"Cell-type-specific Il18/Il18r1/Il18bp mice with epistasis rescue and goblet-cell transcriptional analysis in DSS colitis","pmids":["26638073"],"confidence":"High","gaps":["Transcription factors mediating goblet-cell repression not fully defined","Source of pathogenic IL-18 in colitis left open"]},{"year":2015,"claim":"Placing IL-18 downstream of NLRP1 in metabolism showed inflammasome-derived IL-18 protects against obesity and metabolic syndrome.","evidence":"NLRP1-KO and activating-mutant knock-in mice with IL-18-KO rescue and high-fat-diet phenotyping","pmids":["26603191"],"confidence":"High","gaps":["Target tissue and receptor signaling for metabolic effect undefined","Mechanism of cachexia unresolved"]},{"year":2016,"claim":"Dissecting neonatal sepsis lethality showed IL-18 requires IL-1R1 and acts through IL-17A from γδ T cells and myeloid cells as the downstream effector.","evidence":"IL-18-/- neonatal mice, IL-1R1 KO, IL-17A blockade and blood mRNA analysis","pmids":["27114524"],"confidence":"Medium","gaps":["Mechanistic link between IL-18 and IL-17A induction undefined","Cell-intrinsic vs systemic effects not separated"]},{"year":2017,"claim":"Establishing the type I IFN requirement explained how IL-18 escapes endotoxin tolerance, revealing a regulatory divergence from IL-1β.","evidence":"TLR stimulation of IFN-signaling-deficient macrophages with acute vs chronic stimulation","pmids":["28468974"],"confidence":"Medium","gaps":["Transcription factors integrating TLR and IFN signals not defined","Single lab"]},{"year":2017,"claim":"Defining IL-18-driven ILC3 IL-22 via NF-κB p65 identified a mucosal effector arm with anatomical DC–ILC3 proximity supporting the circuit in human tissue.","evidence":"IL-18 stimulation of human ILC3s, p65 IL22 promoter binding and in situ tonsil immunostaining","pmids":["28842466"],"confidence":"Medium","gaps":["Receptor proximal events to p65 activation in ILC3s undefined","Single lab"]},{"year":2018,"claim":"Cardiac models established inflammasome-derived IL-18 as the dominant cytokine driving myocardial inflammation, fibrosis, and arrhythmogenic electrical remodeling.","evidence":"IL-18-/- and NLRP3-/- mice, IL-18 neutralization and IL-18BP, patch-clamp Ito recordings in isoproterenol and SCD models","pmids":["28549109","33181835"],"confidence":"Medium","gaps":["Signaling pathway from IL-18R to ion channel downregulation undefined","Cell source of cardiac IL-18 not fully resolved"]},{"year":2018,"claim":"Defining the IL-18→IFN-γ axis in MAS established IL-18 as upstream driver of cytokine storm under unopposed signaling.","evidence":"IL-18BP-KO mice with TLR9 stimulation and IL-18R vs IFN-γ blockade","pmids":["29295842"],"confidence":"Medium","gaps":["Cellular IFN-γ source downstream of IL-18 not identified","Single trigger model"]},{"year":2019,"claim":"Linking choline metabolism to inflammasome output showed CTL1-dependent choline uptake supports NLRP3-driven IL-18 production with AMPK/mitophagy feedback termination.","evidence":"CTL1 and choline-kinase inhibition, mitochondrial lipid profiling, AMPK/DRP1 mitophagy assays and IL-18 ELISA","pmids":["30982734"],"confidence":"Medium","gaps":["Direct coupling of mitochondrial state to IL-18 maturation not resolved","Single lab"]},{"year":2020,"claim":"Engineering decoy-resistant IL-18 proved IL-18BP is the limiting brake on antitumor activity, with DR-18 expanding stem-like CD8+ T cells and NK cells in resistant tumors.","evidence":"Directed evolution, IL-18BP binding assays and multiple tumor models with T-cell subset profiling","pmids":["32581358"],"confidence":"High","gaps":["Long-term safety/autoinflammation of unopposed signaling not addressed","Receptor signaling differences from native IL-18 not detailed"]},{"year":2020,"claim":"Establishing the cooperative TLR+IFNα/β requirement in human monocytes and patients confirmed JAK/STAT-dependent IL-18 production and its escape from immunoparalysis, with translational relevance to MAS.","evidence":"Human monocyte stimulation with JAK/STAT inhibitors and IFNβ neutralization, MAS mouse models and patient serum","pmids":["31710506"],"confidence":"Medium","gaps":["Transcriptional integrators of TLR and IFN signals undefined","Patient data limited"]},{"year":2020,"claim":"Identifying enteric neurons as an IL-18 source showed cell-of-origin specificity, with neuronal IL-18 required for goblet-cell antimicrobial peptide production and resistance to invasive infection.","evidence":"Cell-type-specific Il18 deletion, smFISH, RNA-seq/scRNA-seq and Salmonella infection","pmids":["31923399"],"confidence":"High","gaps":["Processing and secretion route of neuronal IL-18 undefined","Receptor signaling driving AMP program not mapped"]},{"year":2023,"claim":"The caspase-4–pro-IL-18 structure resolved how maturation works mechanistically, revealing a binary catalytic-pocket-plus-exosite recognition and propeptide autoinhibition relieved by cleavage to expose receptor-binding sites.","evidence":"Crystal structure, in vitro cleavage, exosite mutagenesis and bacterial infection models","pmids":["37993714"],"confidence":"High","gaps":["Species difference between human caspase-4 and mouse caspase-11 not fully explained mechanistically","Structure of mature IL-18:receptor complex not determined here"]},{"year":2024,"claim":"Connecting metabolism to transcription showed GFPT2-driven O-GlcNAcylation of YBX1 promotes its nuclear translocation to drive IL-18 transcription in pancreatic cancer.","evidence":"Co-IP, mass spectrometry of YBX1 modification, reporter assays and GFPT2 perturbation","pmids":["38575607"],"confidence":"Medium","gaps":["Direct YBX1 binding to the IL-18 promoter not fully mapped","In vivo significance limited"]},{"year":2024,"claim":"Defining the SLC12A3–STING metabolic switch showed IL-18 reprograms macrophages toward fatty acid oxidation via sodium influx and mtDNA-driven STING, sustaining durable intestinal tolerance through a cGAMP/IL-18 feedback loop.","evidence":"Metabolic flux, SLC12A3/STING perturbation, mtDNA and cGAMP measurement in tolerance models","pmids":["38906145"],"confidence":"Medium","gaps":["Receptor-proximal coupling of IL-18R to SLC12A3 activation undefined","Complex multi-cell system"]},{"year":2025,"claim":"Discovering caspase-3-generated short IL-18 redefined IL-18 as functionally bifurcated: a non-secreted 15-kDa nuclear form that bypasses IL-18Rα to drive CDK8-STAT1-ISG15 signaling and NK-cell antitumor activity.","evidence":"Caspase-3 cleavage assays, nuclear fractionation, CDK8 interaction, STAT1 phospho-analysis and syngeneic tumor models","pmids":["39891018"],"confidence":"High","gaps":["How short IL-18 enters the nucleus and engages CDK8 mechanistically undefined","Physiological triggers of caspase-3 cleavage versus inflammasome cleavage unclear"]},{"year":null,"claim":"How a single cytokine's signaling output is contextually partitioned across tissues — p38 versus NF-κB versus STAT3/JNK branches, pro- versus anti-fibrotic and pro- versus antitumor outcomes, and canonical secreted versus nuclear short-IL-18 fates — remains the central unresolved question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model explaining cell-type-specific receptor signaling branch selection","Structure of the mature IL-18:IL-18Rα/β signaling complex not reported in the corpus","Triggers determining caspase-1/4 vs caspase-3 vs granzyme B processing in vivo undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,2,3,17]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,4]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[17,25]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3,14,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,16,35]}],"complexes":["IL-18Rα/IL-18Rβ receptor complex"],"partners":["IL18R1","IL18RAP","IL18BP","CASP1","CASP4","IRAK","TRAF6","GZMB"],"other_free_text":[]}},"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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Crystal structure of the caspase-4–pro-IL-18 complex revealed a binary (two-site) substrate-recognition mechanism: the catalytic pocket engages the tetrapeptide cleavage site while a unique exosite (also used by caspase-1 and caspase-5) binds a structure formed jointly by the propeptide and post-cleavage-site sequences. Pro-IL-18 harbors autoinhibitory interactions between its propeptide and post-cleavage-site region that prevent IL-18Rα binding; caspase-1/4/5 cleavage induces conformational changes generating two critical receptor-binding sites.\",\n      \"method\": \"Crystal structure of caspase-4–pro-IL-18 complex; in vitro cleavage assays; mutagenesis of exosite; bacterial infection cell models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation, in vitro reconstitution, and mutagenesis in a single rigorous study\",\n      \"pmids\": [\"37993714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"IL-18 precursor (pro-IL-18) is biologically inactive and requires cleavage by caspase-1 (ICE) to generate the active mature cytokine. The processed mature IL-18 adopts an all-beta-pleated-sheet fold similar to IL-1β.\",\n      \"method\": \"In vitro caspase-1 cleavage assay; structural comparison; functional IFN-γ induction assays\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — replicated across multiple labs, foundational biochemical processing established by in vitro assay and structural analysis\",\n      \"pmids\": [\"9893178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"IL-18 signals through a receptor complex composed of IL-18Rα (binding chain, previously identified as IL-1R-related protein/IL-1Rrp) and IL-18Rβ (signaling chain). The complex recruits IL-1R-activating kinase (IRAK) and TRAF-6, which phosphorylates NF-κB-inducing kinase leading to NF-κB activation.\",\n      \"method\": \"Receptor subunit identification; signal transduction pathway mapping by biochemical assays\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor complex components identified and signaling cascade mapped; replicated across multiple studies\",\n      \"pmids\": [\"9893178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"IL-12 upregulates expression of the IL-18 receptor on IFN-γ-producing cells, explaining the synergism between IL-12 and IL-18 in IFN-γ induction. IL-18 activates NK cells independently of IL-12.\",\n      \"method\": \"Receptor expression analysis; cytokine stimulation assays; T cell and NK cell functional assays\",\n      \"journal\": \"Current opinion in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor upregulation experiment described, synergism mechanistically explained, single review synthesizing original work\",\n      \"pmids\": [\"9638361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In human epithelial cells stably transfected with IL-18Rβ, IL-18 signaling activates p38 MAPK (phosphorylation detectable within 5 min) rather than NF-κB; p38 MAPK inhibition reduced IL-18 activity to background. Unlike IL-1β, IL-18 did not induce IκB degradation or NF-κB reporter activation, explaining the absence of COX-2 induction and failure of IL-18 to cause fever.\",\n      \"method\": \"Stable transfection of IL-18Rβ; p38 MAPK phosphorylation assay; NF-κB reporter assay; specific kinase inhibitors; COX-2 mRNA and PGE2 measurements\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (phospho-assay, reporter assay, inhibitors, mRNA/protein measurements) in a single rigorous study\",\n      \"pmids\": [\"15161979\"],\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 canonical 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, facilitates STAT1 phosphorylation at Ser727 via CDK8, and enhances ISG15 expression and secretion, mobilizing NK cells with increased cytotoxicity against tumors.\",\n      \"method\": \"Caspase-3 cleavage assays; nuclear fractionation; IL-18Rα binding assays; CDK8 interaction studies; STAT1 phosphorylation analysis; syngeneic tumor models; mouse genetics\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — novel cleavage product characterized biochemically with multiple orthogonal methods and in vivo validation\",\n      \"pmids\": [\"39891018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Bcl6 is a transcriptional repressor of IL-18. Bcl6-binding DNA sequences (IL-18BS) were identified upstream of exon 1 of murine IL-18 and in the promoter of human IL-18. Bcl6 binding to IL-18BS in resting macrophages was demonstrated by gel retardation and chromatin immunoprecipitation; binding diminished after LPS stimulation despite constant Bcl6 protein levels, indicating functional modification of Bcl6 post-stimulation. IL-18BS was required for Bcl6-mediated repression of an IL-18 promoter-luciferase reporter.\",\n      \"method\": \"Gel retardation (EMSA); chromatin immunoprecipitation (ChIP); luciferase reporter assay; dominant-negative Bcl6 transfection; Bcl6-/- macrophages\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (EMSA, ChIP, reporter assay, KO cells) in a single study\",\n      \"pmids\": [\"12817026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Type I IFN (IFNα/β) signaling is essential for IL-18 induction in macrophages: macrophages lacking type I IFN signaling are impaired in IL-18 induction after TLR stimulation. IL-18 expression is sustained after chronic TLR stimulation (escaping endotoxin tolerance) while IL-1β is not, revealing a fundamental regulatory difference.\",\n      \"method\": \"TLR stimulation of macrophages; IFN signaling-deficient macrophages; cytokine mRNA and protein measurement; chronic vs. acute TLR stimulation\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO/deficient-cell experiments with defined phenotypic readout, single lab, two orthogonal approaches\",\n      \"pmids\": [\"28468974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-18 production from human monocytes requires cooperative TLR and IFNα/β signaling; JAK/STAT inhibition or IFNβ neutralization during LPS stimulation blunted IL-18 expression. This mechanism was confirmed in two MAS mouse models and a patient, where JAK/STAT inhibition reduced IL-18 serum levels. IL-18 (but not IL-1β) expression escapes LPS-induced immunoparalysis.\",\n      \"method\": \"Primary human monocyte stimulation; JAK/STAT inhibitors; IFNβ neutralization; MAS mouse models; patient serum analysis\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition and neutralization experiments in vitro and in vivo, translated to patient data\",\n      \"pmids\": [\"31710506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-18 signaling in intestinal epithelial cells (IECs) drives colitis and inhibits goblet cell maturation by regulating the transcriptional program instructing goblet cell development. Deletion of Il18 or Il18r1 specifically in IECs protected mice from colitis; deletion of IL-18 negative regulator Il18bp caused severe colitis with goblet cell loss, which was rescued in Il18bp−/−;Il18r(ΔEC) mice, placing colitis severity at the level of IL-18 signaling in IECs.\",\n      \"method\": \"Conditional knockout mice (Il18 ΔEC, Il18r1 ΔEC, Il18bp−/−); double-mutant epistasis; goblet cell transcriptional program analysis; DSS colitis model\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with genetic epistasis rescue experiment defining pathway position, published in Cell\",\n      \"pmids\": [\"26638073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Enteric neurons (not immune or epithelial cells) are a source of IL-18 and this neuronal IL-18 is specifically required for homeostatic goblet cell antimicrobial protein (AMP) production. Deletion of IL-18 from enteric neurons alone rendered mice susceptible to invasive Salmonella typhimurium infection.\",\n      \"method\": \"Cell-type-specific Il18 deletion; smFISH for IL-18 mRNA in neurons; RNA-seq and single-cell sequencing; bacterial infection model\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO with defined functional phenotype and RNA-seq mechanistic follow-up\",\n      \"pmids\": [\"31923399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NLRP1 inflammasome activation is the upstream regulator that produces IL-18 to prevent obesity and metabolic syndrome. Mice lacking NLRP1 phenocopy IL-18-deficient mice (spontaneous obesity, lipid accumulation); mice with an activating NLRP1 mutation and elevated IL-18 are resistant to diet-induced obesity; fatal cachexia in these mice on high-fat diet is prevented by genetic IL-18 deletion, placing IL-18 downstream of NLRP1.\",\n      \"method\": \"NLRP1 KO and activating-mutation knock-in mice; IL-18 KO rescue; high-fat diet metabolic phenotyping; genetic epistasis\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic epistasis with multiple KO and knock-in lines, metabolic phenotype clearly defined\",\n      \"pmids\": [\"26603191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human peripheral blood neutrophils constitutively express IL-18Rα and IL-18Rβ and respond directly to IL-18 by releasing cytokines/chemokines (protein-synthesis dependent), upregulating CD11b, inducing granule release, and enhancing respiratory burst. IL-18 administration in vivo promoted neutrophil accumulation; IL-18 neutralization suppressed carrageenan-induced footpad inflammation and reduced tissue MPO and TNF-α.\",\n      \"method\": \"Flow cytometry for IL-18R expression; IL-18 stimulation of isolated neutrophils; protein synthesis inhibitor controls; in vivo carrageenan inflammation model; IL-18 neutralizing antibody\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor expression plus functional in vitro and in vivo experiments in a 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) cascade: IL-18-induced neutrophil recruitment and LTB4 production were blocked by anti-TNF-α antibody or absence of TNFRp55, and by the LTB4 synthesis inhibitor MK-886 or LTB4 receptor antagonist. Human neutrophils activated by IL-18 also produced LTB4.\",\n      \"method\": \"Peritoneal neutrophil recruitment assay; TNFRp55-/- mice; LTB4 inhibitor MK-886; LTB4 receptor antagonist; anti-TNF-α neutralization; IL-18-dependent collagen-induced arthritis model\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological dissection of pathway in vivo and in vitro, single lab\",\n      \"pmids\": [\"12847274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-18 bridges innate and adaptive immunity independently of IL-12 by inducing OX40L on dendritic cells; peptide stimulation induces CD134 (OX40) on antigen-specific T cells. CD134 blockade inhibited T cell effector expansion and reduced IFN-γ super-producers by 12-fold. The effect required host-derived IFN-γ but not NK cells or IL-12.\",\n      \"method\": \"In vivo mouse immunization; CD134 blockade; IFN-γ−/− mice; NK cell depletion; IL-12 blockade; T cell clonal expansion assays\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and antibody-blockade epistasis in vivo, multiple controls, single lab\",\n      \"pmids\": [\"16785519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL-18 and IL-1β are independently regulated downstream of NLRP3 inflammasome activation: ROS production (via caspase-11) is required for IL-1β secretion but not IL-18 secretion. Caspase-11-deficient DCs failed to secrete IL-1β in response to Listeria p60 but retained full IL-18 secretion.\",\n      \"method\": \"NLRP3 inflammasome activation with Listeria p60; ROS inhibitors; caspase-11-deficient DCs; ELISA for IL-1β and IL-18\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO and pharmacological dissection showing independent licensing, single lab\",\n      \"pmids\": [\"23028835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In IL-18-deficient mice with CAPS-associated NLRP3 mutations, IL-18 receptor deletion provided greater phenotypic rescue (abolished skin and visceral disease, normalized serum cytokines) than IL-1R deletion at early stages, demonstrating distinct roles for IL-18 vs. IL-1β in CAPS pathology. Persistent inflammation in double-cytokine receptor KO CAPS mice implicated caspase-1-mediated pyroptosis as an additional pathway.\",\n      \"method\": \"CAPS mouse models bred onto Il18r-null and Il1r-null backgrounds; phenotypic and cytokine analyses; genetic epistasis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous genetic epistasis with multiple KO combinations, clear phenotypic rescue hierarchy established\",\n      \"pmids\": [\"24084736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-18BP is a high-affinity naturally occurring binding protein that neutralizes IL-18 in the fluid phase, balancing its biological activity. Human IL-18BP and orthopoxvirus homologs bind both human and murine IL-18 with measurable dissociation constants (viral proteins show 12–50-fold lower Kd for murine vs. human IL-18); binding inhibits IFN-γ induction by IL-18.\",\n      \"method\": \"Surface plasmon resonance (SPR/Biacore) affinity measurements; IFN-γ induction bioassay inhibition\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — SPR quantitative binding measurements plus functional bioassay, rigorous biophysical method\",\n      \"pmids\": [\"11145885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Inflammasome-dependent IL-18 (not IL-1β) is the critical upstream regulator of chemokine expression and macrophage infiltration in the myocardium upon acute β1-AR/ROS signaling by isoproterenol. Genetic deletion of IL-18 or NLRP3 significantly attenuated chemokine expression and macrophage infiltration. IL-18 neutralizing antibodies selectively abated proinflammatory cytokines but not growth factors, and early IL-18 blockade prevented cardiac fibrosis.\",\n      \"method\": \"Cytokine array; IL-18−/− and NLRP3−/− mice; IL-18 neutralizing antibodies; isoproterenol model; histology for fibrosis and macrophage infiltration\",\n      \"journal\": \"European heart journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and antibody blockade with defined cellular phenotype, single lab\",\n      \"pmids\": [\"28549109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-18 induces osteopontin (OPN) expression in cardiac fibroblasts via IRF1 transcription factor, leading to interstitial fibrosis and diastolic dysfunction. Blockade of the IL-18 receptor abolished conditioned-medium-induced OPN upregulation; IRF1 mutation or siRNA reduced IL-18 and OPN in cardiac fibroblasts; IRF1-mutant mice showed downregulated IL-18/OPN and reduced fibrosis under pressure overload.\",\n      \"method\": \"Recombinant IL-18 treatment of cardiac fibroblasts; IL-18R neutralizing antibody; IRF1 siRNA knockdown; IRF1-mutant mice; pressure/volume overload models; Western blot/qPCR\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor blockade, siRNA, and KO mouse converging on same mechanism, single lab\",\n      \"pmids\": [\"19429811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL-18 induces profibrotic changes in renal tubular epithelial cells (HK-2) via STAT3 activation: IL-18 increased phospho-STAT3, SOCS3, α-SMA, collagen III expression and TEC apoptosis in vitro, effects significantly diminished by the STAT3 inhibitor S3I-201. In vivo, IL-18 neutralization (via IL-18BP transgene) reduced p-STAT3 after ureteral obstruction.\",\n      \"method\": \"IL-18 stimulation of HK-2 cells; STAT3 inhibitor S3I-201; Western blotting for p-STAT3; IL-18BP transgenic mice with ureteral obstruction\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro pharmacological inhibition plus in vivo transgenic confirmation, single lab\",\n      \"pmids\": [\"23904224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-18 downregulates type I and III collagen production in human dermal fibroblasts through Ets-1 transcription factor and ERK pathway activation: ERK phosphorylation occurred within 10 min of IL-18 treatment; ERK inhibitor PD98059 blocked IL-18's inhibitory effect on collagen; Ets-1 siRNA knockdown abolished IL-18-regulated collagen suppression.\",\n      \"method\": \"ERK phosphorylation assay; PD98059 ERK inhibitor; Ets-1 siRNA; collagen gene expression and protein measurement; primary dermal fibroblast and SSc fibroblast cultures\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA and pharmacological inhibitor converging on Ets-1/ERK pathway, single lab\",\n      \"pmids\": [\"19865096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-18 acts synergistically with IL-15 to stimulate NK cell proliferation in vitro through direct stimulation of NK cells rather than via an intermediary cell type (shown using an NK cell line).\",\n      \"method\": \"In vitro NK cell proliferation assay; NK cell line (excluding indirect signaling); IL-18 + IL-15 co-stimulation\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean in vitro demonstration with cell-line control excluding indirect mechanism, single lab single method\",\n      \"pmids\": [\"17052916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-18 drives ILC3 proliferation and IL-22 production via NF-κB: the p65 NF-κB subunit binds the proximal IL22 promoter and promotes transcriptional activity downstream of IL-18 signaling. CD11c+ dendritic cells expressing IL-18 were found adjacent to ILC3s in human tonsils in situ.\",\n      \"method\": \"IL-18 stimulation of human ILC3s; NF-κB pathway analysis; p65 promoter binding (ChIP/reporter); in situ human tonsil immunostaining\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter binding and NF-κB pathway mechanistic experiments plus in situ tissue validation, single lab\",\n      \"pmids\": [\"28842466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD8+ T cell-derived granzyme B cleaves keratinocyte pro-IL-18 into its active form; co-culture of granzyme B+/caspase-1− CD8+ T cells with IFN-γ-treated HaCaT keratinocytes resulted in GrB transfer into keratinocytes and increased mature IL-18 in culture supernatant.\",\n      \"method\": \"CD8+ T cell/HaCaT keratinocyte co-culture; flow cytometry for intracellular GrB; ELISA for mature IL-18; GrB+/caspase-1− T cell validation by PCR\",\n      \"journal\": \"Archives of dermatological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-culture experiment with protein transfer and mature IL-18 measurement, single lab\",\n      \"pmids\": [\"23820889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"IFN-γ induces expression and secretion of IL-18 binding protein (IL-18BPa) from human colon carcinoma/epithelial cells (DLD-1, LoVo, Caco-2, HCT116) and keratinocytes (HaCaT); secreted IL-18BPa significantly impaired IL-18/IL-12-stimulated IFN-γ release from PBMC. Sodium butyrate suppressed IFN-γ-induced IL-18BPa but not IL-18 expression, suggesting context-dependent modulation.\",\n      \"method\": \"IFN-γ stimulation; IL-18BPa mRNA and protein measurement; functional IFN-γ production bioassay; sodium butyrate treatment; organ cultures from intestinal biopsies\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — induction and functional neutralization demonstrated in multiple cell lines plus ex vivo tissue, single lab\",\n      \"pmids\": [\"11739524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In pancreatic cancer cells, GFPT2-mediated O-GlcNAcylation promotes nuclear translocation of YBX1, which then functions as a transcription factor to promote IL-18 transcription, linking HBP metabolism to IL-18-dependent immune microenvironment regulation.\",\n      \"method\": \"Co-IP; protein mass spectrometry identifying YBX1 O-GlcNAcylation; transcriptional reporter assays; GFPT2 KO/knockdown; cellular proteomics\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and MS identification of modification plus functional transcriptional assay, single lab\",\n      \"pmids\": [\"38575607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-18 stimulation activates SLC12A3 (NCC) in macrophages, leading to sodium influx, mitochondrial DNA release, and STING activation, reprogramming macrophages from glycolysis to fatty acid oxidation (FAO). This metabolic switch is maintained by a bistable feedback loop involving macrophage-derived 2'3'-cGAMP and epithelial IL-18, encoding durable intestinal immune tolerance.\",\n      \"method\": \"Metabolic flux analysis; SLC12A3 inhibition/KO; STING KO; mitochondrial DNA measurement; cGAMP measurement; intestinal tolerance models\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic and pharmacological perturbations establishing pathway order, single lab, complex in vivo system\",\n      \"pmids\": [\"38906145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-18 produced by tumor cells promotes the development of NK-cell-controlled metastases in a PD-1-dependent manner; IL-18 upregulates PD-1 on mature NK cells in lymphoid organs of tumor-bearing mice. RNAi knockdown of IL-18 in tumors or systemic depletion by IL-18BP stimulated NK cell-dependent immunosurveillance.\",\n      \"method\": \"Tumor-derived IL-18 knockdown (RNAi); IL-18BP depletion; PD-1 expression analysis on NK cells; PD-1-deficient mice; metastasis models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi and neutralization approaches with KO mice establishing PD-1 dependence, single lab\",\n      \"pmids\": [\"21724589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-18BP is frequently upregulated in tumors and limits IL-18 anti-tumor activity. A directed-evolution-engineered 'decoy-resistant' IL-18 (DR-18) maintains IL-18R signaling but is impervious to IL-18BP inhibition; DR-18 promoted poly-functional effector CD8+ T cells, reduced TOX+ exhausted CD8+ T cells, expanded TCF1+ stem-like CD8+ T cells, and enhanced NK cell activity in anti-PD-1-resistant tumors lacking MHC-I.\",\n      \"method\": \"Directed evolution; IL-18BP binding assays; mouse tumor models; flow cytometry for T cell subsets; comparison with wild-type IL-18\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — engineered variant with mechanistic binding characterization, multiple in vivo tumor models, and defined immune cell phenotypes\",\n      \"pmids\": [\"32581358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-18-mediated lethality in neonatal sepsis requires IL-1R1 signaling (not adaptive immunity) and depends on IL-17A produced by intestinal γδT cells and Ly6G+ myeloid cells. IL-18 administration increased IL-17A production, and blocking IL-17A reduced IL-18-potentiated mortality in both neonatal sepsis and endotoxemia, placing IL-17A as an effector downstream of IL-18.\",\n      \"method\": \"IL-18−/− neonatal mice; IL-1R1 KO; γδT cell analysis; IL-17A blockade; genome-wide blood mRNA analysis from septic neonates\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and cytokine blockade defining pathway order in vivo, single lab\",\n      \"pmids\": [\"27114524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IL-18 is constitutively expressed specifically in the intercalated cells of the late distal convoluted tubule, connecting tubule, and collecting duct of the healthy human kidney. These same cells also express caspase-1 and P2X7 receptor (both required for IL-18 processing and secretion), establishing the cellular machinery for IL-18 activation at this site.\",\n      \"method\": \"In situ hybridization; immunohistochemistry with cell-type markers (calbindin-D28k, aquaporin-2, vacuolar H+-ATPase); confocal microscopy; Western blot; PCR\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal localization methods with co-localization of processing machinery, single lab\",\n      \"pmids\": [\"17687255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-18 reduces UV-induced DNA damage in keratinocytes and prevents photoimmunosuppression via promotion of DNA repair; the effect was absent in Xpa-knockout (DNA repair-deficient) mice, demonstrating dependence on nucleotide excision repair. Unlike IL-12, IL-18 did not break UV-induced immunotolerance mediated by regulatory T cells.\",\n      \"method\": \"UV irradiation of mice; IL-18 injection; apoptosis and DNA damage immunohistochemistry; Xpa-KO mice; contact hypersensitivity readout\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO (Xpa) establishing DNA repair dependence, in vivo functional assay, single lab\",\n      \"pmids\": [\"16493047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-18 reduces voltage-gated potassium channel (Ito current) expression in cardiomyocytes, causing electrical remodeling and ventricular tachycardia. Sustained IL-18 inhibition with IL-18BP in SCD mice decreased cardiac fibrosis, NF-κB phosphorylation, improved diastolic function, and attenuated VT; recombinant IL-18 administered to isolated hearts triggered VT from the right ventricle.\",\n      \"method\": \"SCD humanized mouse model; IL-18BP treatment; patch-clamp recording of Ito; recombinant IL-18 in isolated hearts; NF-κB phosphorylation assay; echocardiography\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ex vivo IL-18 administration plus in vivo inhibition with defined electrophysiological readout, single lab\",\n      \"pmids\": [\"33181835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-18 enhances thrombospondin-1 (TSP-1) production in human gastric cancer cells in a dose- and time-dependent manner via JNK pathway activation: SP600125 (JNK inhibitor) blocked IL-18-enhanced TSP-1 expression; IL-18 increased phosphorylated JNK as detected by Western blot.\",\n      \"method\": \"RT-PCR; ELISA; JNK inhibitor SP600125; phospho-JNK Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological inhibitor with signaling readout, single lab, single cytokine pathway\",\n      \"pmids\": [\"16650813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Unopposed IL-18 signaling (in IL-18BP-deficient mice) drives severe MAS upon TLR9 stimulation, with IL-18 acting upstream of IFN-γ. Blocking IL-18 receptor signaling attenuated MAS severity and IFN-γ responses; blocking IFN-γ had comparable effects, establishing the IL-18→IFN-γ axis in MAS pathogenesis.\",\n      \"method\": \"IL-18BP-KO mice; TLR9/CpG stimulation; IL-18R blockade; IFN-γ blockade; serum cytokine and IFN-γ signature gene analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus antibody blockade epistasis in vivo, single lab\",\n      \"pmids\": [\"29295842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Langerhans cell-derived IL-18, processed by caspase-1, contributes to contact hypersensitivity initiation: caspase-1−/− mice had impaired IFN-γ production from LN cells that was restored by exogenous IL-18; CHS responses were inhibited by anti-IL-18 antibody and in caspase-1−/− mice; migratory hapten-modified LC in LN expressed high IL-18 mRNA and secreted functional IL-18.\",\n      \"method\": \"Caspase-1-KO mice; exogenous IL-18 rescue; anti-IL-18 neutralizing antibody; CHS in vivo model; mRNA expression in LN cells\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with exogenous rescue plus antibody blockade, single lab\",\n      \"pmids\": [\"11907086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Choline uptake via CTL1 transporter in macrophages supports NLRP3 inflammasome activation and IL-18 production; inhibition of CTL1 or choline kinase altered mitochondrial lipid profile, attenuated mitochondrial ATP synthesis, and activated AMPK, which stimulates DRP1-mediated mitophagy to terminate NLRP3 inflammasome activation.\",\n      \"method\": \"CTL1 inhibition/knockdown; choline kinase inhibitors; mitochondrial lipid profiling; AMPK activation assay; DRP1 mitochondrial recruitment; mitophagy assay; IL-18 ELISA\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays defining metabolic pathway upstream of IL-18, single lab\",\n      \"pmids\": [\"30982734\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-18 is synthesized as an inactive precursor constitutively present in most cells; it is cleaved into its active 18-kDa mature form primarily by caspase-1 (canonical inflammasome) and also by caspase-4/5 (noncanonical inflammasome) at the same tetrapeptide site via a binary recognition mechanism (catalytic pocket plus exosite), or by extracellular proteases such as granzyme B; caspase-3 generates a distinct 15-kDa nuclear 'short IL-18' that does not bind IL-18Rα but instead activates CDK8-STAT1-ISG15 signaling to mobilize NK cells. Mature IL-18 signals through a heterodimeric receptor (IL-18Rα/IL-18Rβ), primarily via p38 MAPK (and secondarily NF-κB in some contexts), to drive IFN-γ production from T and NK cells (synergistically with IL-12, which upregulates IL-18R), neutrophil activation via TNF-α/LTB4, ILC3 IL-22 production via NF-κB/p65, and OX40L induction on dendritic cells. Its activity is tightly neutralized by the high-affinity soluble decoy IL-18BP, which is induced by IFN-γ and IL-27. Transcriptionally, IL-18 expression is constitutively driven and repressed by Bcl6 (which binds an IL-18BS element in the promoter), and its induction requires cooperative TLR and type I IFN/JAK-STAT signaling that escapes endotoxin tolerance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL-18 is a constitutively expressed proinflammatory cytokine of the IL-1 family that bridges innate and adaptive immunity, acting as a central upstream driver of IFN-\\u03b3 responses, tissue homeostasis, and inflammatory pathology [#1, #9]. It is synthesized as an inactive precursor whose propeptide and post-cleavage-site sequences engage in autoinhibitory interactions that occlude IL-18R\\u03b1 binding; proteolytic maturation relieves this autoinhibition and generates two receptor-binding surfaces [#0]. Canonical activation is performed by caspase-1, which cleaves pro-IL-18 to the active 18-kDa cytokine [#1], while the human noncanonical inflammasome caspase-4 (but not mouse caspase-11) cleaves at the identical tetrapeptide site through a binary mechanism combining the catalytic pocket with an exosite shared by caspase-1/4/5 [#0]; extracellular maturation is achieved by CD8+ T-cell granzyme B transferred into target cells [#24]. Mature IL-18 signals through the heterodimeric IL-18R\\u03b1/IL-18R\\u03b2 receptor, recruiting IRAK and TRAF6 [#2] and signaling predominantly via p38 MAPK rather than NF-\\u03baB, a feature that distinguishes it from IL-1\\u03b2 and explains its failure to induce COX-2 or fever [#4]. Receptor engagement drives IFN-\\u03b3 production synergistically with IL-12 (which upregulates the IL-18 receptor) [#3], NK-cell proliferation and activity [#22], ILC3 IL-22 production via NF-\\u03baB p65 [#23], OX40L-dependent T-cell priming [#14], and direct neutrophil activation through a TNF-\\u03b1\\u2192LTB4 cascade [#12, #13]. IL-18 activity is governed transcriptionally by Bcl6 repression at an IL-18BS promoter element [#6] and by cooperative TLR plus type I IFN/JAK-STAT signaling that allows IL-18 to escape endotoxin tolerance [#7, #8], and post-translationally by the high-affinity soluble decoy IL-18BP, which is induced by IFN-\\u03b3 [#17, #25]. Genetic epistasis places IL-18 downstream of the NLRP1 and NLRP3 inflammasomes in metabolic and autoinflammatory disease, including macrophage activation syndrome via an IL-18\\u2192IFN-\\u03b3 axis [#11, #16, #35], and at the epithelial interface IL-18 controls goblet-cell programs, antimicrobial defense, and intestinal tolerance [#9, #10, #27]. A distinct caspase-3\\u2013generated 15-kDa 'short IL-18' does not bind IL-18R\\u03b1 but translocates to the nucleus to drive CDK8-dependent STAT1 Ser727 phosphorylation and ISG15 expression, mobilizing antitumor NK cells [#5]. Engineered decoy-resistant IL-18 that evades IL-18BP enhances stem-like CD8+ T-cell and NK-cell antitumor immunity, defining IL-18BP as a key brake on its therapeutic activity [#29].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing why IL-12 and IL-18 synergize for IFN-\\u03b3 answered how two distinct cytokines cooperate, showing IL-12 upregulates the IL-18 receptor on IFN-\\u03b3-producing cells while IL-18 can activate NK cells independently.\",\n      \"evidence\": \"Receptor expression analysis and T/NK cell functional assays\",\n      \"pmids\": [\"9638361\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Synthesized within a review rather than a single primary dataset\", \"Does not define the receptor signaling branch driving IFN-\\u03b3\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defining pro-IL-18 maturation and the receptor complex established the core activation logic: caspase-1 cleavage of an inactive precursor yields an IL-1\\u03b2-like cytokine that signals through IL-18R\\u03b1/IL-18R\\u03b2 via IRAK/TRAF6 to NF-\\u03baB.\",\n      \"evidence\": \"In vitro caspase-1 cleavage, structural comparison, receptor subunit identification, and signal-transduction mapping\",\n      \"pmids\": [\"9893178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of propeptide autoinhibition\", \"NF-\\u03baB assignment later refined to p38 MAPK in epithelial contexts\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Quantifying IL-18BP binding defined the principal extracellular brake on IL-18, showing high-affinity neutralization of both human and murine IL-18 by host and viral decoy proteins.\",\n      \"evidence\": \"Surface plasmon resonance affinity measurements with IFN-\\u03b3 induction bioassay\",\n      \"pmids\": [\"11145885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address in vivo regulation of IL-18BP abundance\", \"Structural basis of the IL-18:IL-18BP interface not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying IFN-\\u03b3-induced IL-18BP from epithelial cells defined a negative feedback loop, linking IL-18-driven IFN-\\u03b3 to its own neutralization.\",\n      \"evidence\": \"IFN-\\u03b3 stimulation with IL-18BPa measurement and IFN-\\u03b3 production bioassays in cell lines and intestinal organ cultures\",\n      \"pmids\": [\"11739524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish the in vivo physiological consequence of the feedback\", \"Mechanism of butyrate modulation undefined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrating direct neutrophil responsiveness answered whether IL-18 acts on innate effectors directly, showing constitutive IL-18R expression and functional activation of neutrophils plus a role in acute inflammation.\",\n      \"evidence\": \"Flow cytometry, neutrophil stimulation with synthesis-inhibitor controls, and in vivo carrageenan model with IL-18 neutralization\",\n      \"pmids\": [\"11509635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define downstream signaling in neutrophils\", \"Effector mediators of recruitment unresolved until later work\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showing Langerhans-cell IL-18 drives contact hypersensitivity established caspase-1-processed IL-18 as an initiator of cutaneous adaptive immunity.\",\n      \"evidence\": \"Caspase-1-KO mice with exogenous IL-18 rescue and anti-IL-18 neutralization in a CHS model\",\n      \"pmids\": [\"11907086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the receptor signaling branch in this setting\", \"Cellular target of IL-18 in the lymph node not pinpointed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identifying Bcl6 as a promoter repressor answered how constitutive IL-18 transcription is restrained, showing LPS-induced loss of Bcl6 occupancy at the IL-18BS element derepresses the gene.\",\n      \"evidence\": \"EMSA, ChIP, luciferase reporter, dominant-negative Bcl6, and Bcl6-/- macrophages\",\n      \"pmids\": [\"12817026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Post-stimulation modification of Bcl6 not molecularly defined\", \"Did not connect to type I IFN co-regulation later identified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Dissecting the TNF-\\u03b1\\u2192LTB4 cascade defined the mechanism by which IL-18 recruits neutrophils, ordering soluble mediators downstream of receptor engagement.\",\n      \"evidence\": \"TNFRp55-/- mice, anti-TNF-\\u03b1, LTB4 synthesis/receptor antagonists in peritoneal recruitment and arthritis models\",\n      \"pmids\": [\"12847274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell source of TNF-\\u03b1 in the cascade not pinned\", \"Intracellular signaling linking IL-18R to LTB4 synthesis undefined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolving the dominant signaling branch reconciled IL-18's non-pyrogenic phenotype, showing rapid p38 MAPK activation without I\\u03baB degradation or NF-\\u03baB reporter activity, unlike IL-1\\u03b2.\",\n      \"evidence\": \"Stable IL-18R\\u03b2 transfection, phospho-p38 assay, NF-\\u03baB reporter, kinase inhibitors, COX-2/PGE2 measurement\",\n      \"pmids\": [\"15161979\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Context dependence of NF-\\u03baB vs p38 across cell types not resolved\", \"Used a transfected epithelial system\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defining the OX40L/CD134 axis showed how IL-18 links innate signals to T-cell expansion independently of IL-12 and NK cells, while requiring host IFN-\\u03b3.\",\n      \"evidence\": \"In vivo immunization with CD134 blockade, IFN-\\u03b3-/- mice, NK depletion, and IL-12 blockade\",\n      \"pmids\": [\"16785519\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect induction of dendritic-cell OX40L not separated\", \"Receptor signaling pathway in this context unmapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showing direct IL-15 synergy on an NK cell line established that IL-18-driven NK proliferation is cell-intrinsic rather than mediated by an intermediary cell.\",\n      \"evidence\": \"In vitro NK cell-line proliferation with IL-18 + IL-15 co-stimulation\",\n      \"pmids\": [\"17052916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single in vitro method\", \"Molecular basis of IL-18/IL-15 synergy undefined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linking IL-18 to UV-induced DNA repair showed a protective, repair-dependent role in keratinocytes distinct from immunosuppressive cytokines.\",\n      \"evidence\": \"UV irradiation of mice with IL-18 injection and Xpa-KO repair-deficient mice with contact hypersensitivity readout\",\n      \"pmids\": [\"16493047\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between IL-18 signaling and nucleotide excision repair unresolved\", \"Receptor dependence not directly tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying divergent fibroblast responses showed IL-18 can be pro- or anti-fibrotic depending on tissue, acting via IRF1-osteopontin in cardiac fibroblasts versus Ets-1/ERK suppression of collagen in dermal fibroblasts.\",\n      \"evidence\": \"IL-18 stimulation with receptor blockade, IRF1 siRNA/mutant mice and Ets-1 siRNA/ERK inhibition in fibroblast cultures and overload models\",\n      \"pmids\": [\"19429811\", \"19865096\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants of opposing fibroblast responses across tissues unexplained\", \"Single-lab mechanisms per tissue\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealing tumor-derived IL-18 induces NK-cell PD-1 uncovered an immunosuppressive arm of IL-18 that promotes metastasis, complicating its antitumor role.\",\n      \"evidence\": \"Tumor IL-18 RNAi, IL-18BP depletion, NK PD-1 analysis, and PD-1-deficient mice in metastasis models\",\n      \"pmids\": [\"21724589\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of PD-1 upregulation by IL-18 undefined\", \"Context distinguishing pro- vs antitumor IL-18 not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Genetic epistasis in CAPS established distinct, non-redundant roles for IL-18 and IL-1\\u03b2, with IL-18R deletion providing greater early rescue and implicating pyroptosis in residual disease.\",\n      \"evidence\": \"CAPS mice on Il18r-null and Il1r-null backgrounds with phenotypic and cytokine analyses\",\n      \"pmids\": [\"24084736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular source of pathogenic IL-18 in CAPS not defined\", \"Residual pyroptotic pathway not molecularly dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defining inflammasome heterogeneity showed IL-18 and IL-1\\u03b2 secretion are independently licensed downstream of NLRP3, with ROS/caspase-11 required for IL-1\\u03b2 but not IL-18.\",\n      \"evidence\": \"Listeria p60 NLRP3 activation, ROS inhibitors, caspase-11-deficient DCs and ELISA\",\n      \"pmids\": [\"23028835\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of differential licensing unresolved\", \"Single stimulus/cell type\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying granzyme B as an extracellular protease that matures pro-IL-18 showed inflammasome-independent activation, with CD8+ T cells processing keratinocyte IL-18.\",\n      \"evidence\": \"CD8+ T cell/HaCaT co-culture with intracellular GrB tracking and mature IL-18 ELISA\",\n      \"pmids\": [\"23820889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cleavage site for granzyme B not mapped\", \"In vivo relevance not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defining IL-18\\u2192STAT3 in renal tubular cells established a profibrotic signaling route in kidney injury distinct from the p38 axis.\",\n      \"evidence\": \"IL-18 stimulation of HK-2 cells with STAT3 inhibitor and IL-18BP transgenic mice in ureteral obstruction\",\n      \"pmids\": [\"23904224\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between IL-18R and STAT3 activation undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Conditional knockouts placed IL-18 signaling within intestinal epithelial cells as a driver of colitis and a repressor of goblet-cell maturation, with IL-18BP loss causing severe disease rescued by epithelial receptor deletion.\",\n      \"evidence\": \"Cell-type-specific Il18/Il18r1/Il18bp mice with epistasis rescue and goblet-cell transcriptional analysis in DSS colitis\",\n      \"pmids\": [\"26638073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factors mediating goblet-cell repression not fully defined\", \"Source of pathogenic IL-18 in colitis left open\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placing IL-18 downstream of NLRP1 in metabolism showed inflammasome-derived IL-18 protects against obesity and metabolic syndrome.\",\n      \"evidence\": \"NLRP1-KO and activating-mutant knock-in mice with IL-18-KO rescue and high-fat-diet phenotyping\",\n      \"pmids\": [\"26603191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Target tissue and receptor signaling for metabolic effect undefined\", \"Mechanism of cachexia unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Dissecting neonatal sepsis lethality showed IL-18 requires IL-1R1 and acts through IL-17A from \\u03b3\\u03b4 T cells and myeloid cells as the downstream effector.\",\n      \"evidence\": \"IL-18-/- neonatal mice, IL-1R1 KO, IL-17A blockade and blood mRNA analysis\",\n      \"pmids\": [\"27114524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between IL-18 and IL-17A induction undefined\", \"Cell-intrinsic vs systemic effects not separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Establishing the type I IFN requirement explained how IL-18 escapes endotoxin tolerance, revealing a regulatory divergence from IL-1\\u03b2.\",\n      \"evidence\": \"TLR stimulation of IFN-signaling-deficient macrophages with acute vs chronic stimulation\",\n      \"pmids\": [\"28468974\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factors integrating TLR and IFN signals not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining IL-18-driven ILC3 IL-22 via NF-\\u03baB p65 identified a mucosal effector arm with anatomical DC\\u2013ILC3 proximity supporting the circuit in human tissue.\",\n      \"evidence\": \"IL-18 stimulation of human ILC3s, p65 IL22 promoter binding and in situ tonsil immunostaining\",\n      \"pmids\": [\"28842466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor proximal events to p65 activation in ILC3s undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Cardiac models established inflammasome-derived IL-18 as the dominant cytokine driving myocardial inflammation, fibrosis, and arrhythmogenic electrical remodeling.\",\n      \"evidence\": \"IL-18-/- and NLRP3-/- mice, IL-18 neutralization and IL-18BP, patch-clamp Ito recordings in isoproterenol and SCD models\",\n      \"pmids\": [\"28549109\", \"33181835\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway from IL-18R to ion channel downregulation undefined\", \"Cell source of cardiac IL-18 not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defining the IL-18\\u2192IFN-\\u03b3 axis in MAS established IL-18 as upstream driver of cytokine storm under unopposed signaling.\",\n      \"evidence\": \"IL-18BP-KO mice with TLR9 stimulation and IL-18R vs IFN-\\u03b3 blockade\",\n      \"pmids\": [\"29295842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular IFN-\\u03b3 source downstream of IL-18 not identified\", \"Single trigger model\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linking choline metabolism to inflammasome output showed CTL1-dependent choline uptake supports NLRP3-driven IL-18 production with AMPK/mitophagy feedback termination.\",\n      \"evidence\": \"CTL1 and choline-kinase inhibition, mitochondrial lipid profiling, AMPK/DRP1 mitophagy assays and IL-18 ELISA\",\n      \"pmids\": [\"30982734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct coupling of mitochondrial state to IL-18 maturation not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Engineering decoy-resistant IL-18 proved IL-18BP is the limiting brake on antitumor activity, with DR-18 expanding stem-like CD8+ T cells and NK cells in resistant tumors.\",\n      \"evidence\": \"Directed evolution, IL-18BP binding assays and multiple tumor models with T-cell subset profiling\",\n      \"pmids\": [\"32581358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term safety/autoinflammation of unopposed signaling not addressed\", \"Receptor signaling differences from native IL-18 not detailed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing the cooperative TLR+IFN\\u03b1/\\u03b2 requirement in human monocytes and patients confirmed JAK/STAT-dependent IL-18 production and its escape from immunoparalysis, with translational relevance to MAS.\",\n      \"evidence\": \"Human monocyte stimulation with JAK/STAT inhibitors and IFN\\u03b2 neutralization, MAS mouse models and patient serum\",\n      \"pmids\": [\"31710506\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional integrators of TLR and IFN signals undefined\", \"Patient data limited\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying enteric neurons as an IL-18 source showed cell-of-origin specificity, with neuronal IL-18 required for goblet-cell antimicrobial peptide production and resistance to invasive infection.\",\n      \"evidence\": \"Cell-type-specific Il18 deletion, smFISH, RNA-seq/scRNA-seq and Salmonella infection\",\n      \"pmids\": [\"31923399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Processing and secretion route of neuronal IL-18 undefined\", \"Receptor signaling driving AMP program not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The caspase-4\\u2013pro-IL-18 structure resolved how maturation works mechanistically, revealing a binary catalytic-pocket-plus-exosite recognition and propeptide autoinhibition relieved by cleavage to expose receptor-binding sites.\",\n      \"evidence\": \"Crystal structure, in vitro cleavage, exosite mutagenesis and bacterial infection models\",\n      \"pmids\": [\"37993714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Species difference between human caspase-4 and mouse caspase-11 not fully explained mechanistically\", \"Structure of mature IL-18:receptor complex not determined here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connecting metabolism to transcription showed GFPT2-driven O-GlcNAcylation of YBX1 promotes its nuclear translocation to drive IL-18 transcription in pancreatic cancer.\",\n      \"evidence\": \"Co-IP, mass spectrometry of YBX1 modification, reporter assays and GFPT2 perturbation\",\n      \"pmids\": [\"38575607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct YBX1 binding to the IL-18 promoter not fully mapped\", \"In vivo significance limited\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining the SLC12A3\\u2013STING metabolic switch showed IL-18 reprograms macrophages toward fatty acid oxidation via sodium influx and mtDNA-driven STING, sustaining durable intestinal tolerance through a cGAMP/IL-18 feedback loop.\",\n      \"evidence\": \"Metabolic flux, SLC12A3/STING perturbation, mtDNA and cGAMP measurement in tolerance models\",\n      \"pmids\": [\"38906145\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor-proximal coupling of IL-18R to SLC12A3 activation undefined\", \"Complex multi-cell system\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovering caspase-3-generated short IL-18 redefined IL-18 as functionally bifurcated: a non-secreted 15-kDa nuclear form that bypasses IL-18R\\u03b1 to drive CDK8-STAT1-ISG15 signaling and NK-cell antitumor activity.\",\n      \"evidence\": \"Caspase-3 cleavage assays, nuclear fractionation, CDK8 interaction, STAT1 phospho-analysis and syngeneic tumor models\",\n      \"pmids\": [\"39891018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How short IL-18 enters the nucleus and engages CDK8 mechanistically undefined\", \"Physiological triggers of caspase-3 cleavage versus inflammasome cleavage unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single cytokine's signaling output is contextually partitioned across tissues — p38 versus NF-\\u03baB versus STAT3/JNK branches, pro- versus anti-fibrotic and pro- versus antitumor outcomes, and canonical secreted versus nuclear short-IL-18 fates — remains the central unresolved question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model explaining cell-type-specific receptor signaling branch selection\", \"Structure of the mature IL-18:IL-18R\\u03b1/\\u03b2 signaling complex not reported in the corpus\", \"Triggers determining caspase-1/4 vs caspase-3 vs granzyme B processing in vivo undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 2, 3, 17]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [17, 25]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 14, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 16, 35]}\n    ],\n    \"complexes\": [\"IL-18R\\u03b1/IL-18R\\u03b2 receptor complex\"],\n    \"partners\": [\"IL18R1\", \"IL18RAP\", \"IL18BP\", \"CASP1\", \"CASP4\", \"IRAK\", \"TRAF6\", \"GZMB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}