Affinage

IL18

Interleukin-18 · UniProt Q14116

Round 2 corrected
Length
193 aa
Mass
22.3 kDa
Annotated
2026-04-28
130 papers in source corpus 40 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL-18 is a pleiotropic pro-inflammatory cytokine of the IL-1 family that orchestrates innate and adaptive immune responses—most prominently IFN-γ production—while also regulating metabolic homeostasis, intestinal epithelial goblet cell maturation, and anti-tumor immunity. Synthesized as an inactive 24-kDa precursor constitutively present in most cell types, pro-IL-18 is processed to its mature 18-kDa form primarily by caspase-1 within NLRP1/NLRP3/NLRC4 inflammasomes, and alternatively by caspase-4/5 via an exosite-dependent mechanism or by granzyme B; the mature form is selectively released through electrostatically filtering GSDMD pores whose negative conduit charge preferentially passes the positively charged mature cytokine (PMID:8999548, PMID:37993714, PMID:33883744). Mature IL-18 signals through the IL-18Rα/IL-18Rβ heterodimer, recruiting MyD88 via the sorting adaptor TRAM to activate NF-κB, AP-1, MAPK (ERK/PI3K-Akt), and STAT1 pathways, thereby synergizing with IL-12 to induce IFN-γ in NK cells, T cells, and B cells, activating neutrophils, promoting dendritic cell maturation, and—in enteric neurons—driving goblet cell antimicrobial peptide production (PMID:7477296, PMID:8766574, PMID:22685567, PMID:31923399, PMID:26638073). A distinct caspase-3-generated 15-kDa nuclear 'short IL-18' activates an IL-18Rα-independent CDK8–STAT1 Ser727–ISG15 pathway that mobilizes NK cell anti-tumor cytotoxicity, while the secreted decoy receptor IL-18BP serves as the dominant negative regulator of canonical extracellular IL-18 bioactivity (PMID:39891018, PMID:32581358).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1995 High

    The identification of IL-18 (IGIF) as a novel cytokine that induces IFN-γ and enhances NK cytotoxicity established its foundational role as a Th1-promoting factor distinct from IL-12.

    Evidence cDNA cloning from murine liver with recombinant protein validation in spleen cell IFN-γ induction and NK cytotoxicity assays

    PMID:7477296

    Open questions at the time
    • No receptor or signaling pathway identified
    • Processing mechanism from precursor unknown
    • Cellular sources not defined beyond liver
  2. 1997 High

    Demonstration that caspase-1 is the principal pro-IL-18 converting enzyme and that IL-18Rα (IL-1Rrp) is the cognate receptor resolved how IL-18 is activated and how it initiates signaling.

    Evidence In vitro caspase-1 cleavage assays, caspase-1 KO mice with diminished serum IL-18/IFN-γ; receptor purification from L428 cells with radioligand binding and COS-1 reconstitution

    PMID:8999548 PMID:9325300

    Open questions at the time
    • Co-receptor (IL-18Rβ) not yet characterized
    • Inflammasome platform identity unknown
    • Mechanism of leaderless secretion unresolved
  3. 1999 High

    IL-18 was shown to act beyond Th1 polarization, co-inducing IL-13 with IL-2 in NK/T cells independently of IFN-γ, and its caspase-1-processed mature form was linked to Crohn's disease mucosal inflammation, broadening its functional scope.

    Evidence NK/T cell stimulation with IFN-γ KO controls for IL-13 induction; Western blot and antisense knockdown in Crohn's disease lamina propria mononuclear cells

    PMID:10227975 PMID:10384110

    Open questions at the time
    • Epithelial cell-intrinsic effects of IL-18 in IBD not dissected
    • Precise Th2 vs. Th1 polarizing conditions incompletely defined
  4. 2000 High

    Elucidation of the IL-18Rα/IL-18Rβ heterodimer signaling through NF-κB and AP-1 via MyD88 established IL-18's signal transduction architecture and its capacity to drive IL-2 production in T cells.

    Evidence IL-18 KO mice, Jurkat cell EMSA/reporter assays, neutralizing antibody depletion of IL-18 from sarcoid fluid

    PMID:10679398 PMID:11035116

    Open questions at the time
    • Role of sorting adaptors (e.g., TRAM) in MyD88 recruitment unknown
    • Downstream transcription factor hierarchy for different cell types unresolved
  5. 2001 High

    IL-18 was shown to directly activate neutrophils and subsequently to drive neutrophil recruitment via a TNF-α→LTB4 axis, extending its function beyond lymphocyte biology to innate granulocyte responses.

    Evidence Neutrophil stimulation assays, in vivo IL-18 neutralization in carrageenan inflammation, TNFRp55 KO mice and LTB4 inhibitors

    PMID:11509635 PMID:12847274

    Open questions at the time
    • Whether IL-18 directly activates other granulocyte types not established
    • Neutrophil IL-18 autocrine loops not explored
  6. 2005 High

    Discovery of polarized IL-18 secretion from dendritic cell lysosomes toward NK cells at the immunological synapse revealed a directed, non-classical release mechanism for this leaderless cytokine.

    Evidence Confocal imaging of DC–NK synapses, Ca2+ chelation and tubulin disruption, synaptic vs. non-synaptic fraction ELISA

    PMID:15802534

    Open questions at the time
    • Molecular identity of the lysosomal IL-18 loading machinery unknown
    • Relationship to later-discovered GSDMD pore-mediated release not addressed
  7. 2007 High

    Mapping of IL-18-activated PI3K/Akt and MEK/ERK pathways converging on NF-κB, STAT1, and IRF-1 to drive chemokine expression in keratinocytes, and the identification of granzyme B as an alternative pro-IL-18 convertase, expanded the signaling and processing repertoire.

    Evidence Kinase inhibitor panel and antisense knockdown in primary keratinocytes; CD8+ T cell/HaCaT co-culture showing GrB-dependent mature IL-18 generation

    PMID:17274000 PMID:23820889

    Open questions at the time
    • Relative contribution of GrB vs. caspase-1 in vivo not quantified
    • Cell-type specificity of PI3K/Akt vs. MAPK engagement not fully explored
  8. 2012 High

    Identification of TRAM as a sorting adaptor that directly binds MyD88-TIR to mediate IL-18 signal transduction resolved a missing link in how IL-18R engagement couples to downstream NF-κB activation.

    Evidence In vitro protein interaction assay, TRAM KO mice, RNAi knockdown, live cell co-localization imaging

    PMID:22685567

    Open questions at the time
    • Structural basis of TRAM–MyD88 interaction at the IL-18R complex not resolved
    • Whether TRAM is required in all IL-18-responsive cell types not tested
  9. 2014 High

    Crystal structures of IL-18 bound to IL-18Rα established that electrostatic surface complementarity determines receptor specificity within the IL-1 family, providing a structural framework for understanding IL-18 signaling and decoy receptor (IL-18BP) inhibition.

    Evidence X-ray crystallography of IL-18/IL-18Rα ectodomain complex

    PMID:25261253

    Open questions at the time
    • Full ternary complex with IL-18Rβ not structurally resolved
    • Conformational changes upon signalosome assembly not captured
  10. 2015 High

    Genetic epistasis in NLRP1 and IL-18 mutant mice established a specific NLRP1→caspase-1→IL-18 axis preventing obesity, while conditional knockout studies revealed that epithelial IL-18 signaling inhibits goblet cell maturation and that IL-18BP is a critical in vivo brake on this process.

    Evidence NLRP1 KO, activating-mutation knock-in, and IL-18 KO mice with metabolic phenotyping; conditional epithelial IL-18R1 and IL-18BP KO mice with DSS colitis and transcriptomics

    PMID:26603191 PMID:26638073

    Open questions at the time
    • Precise transcriptional targets by which IL-18 suppresses goblet cell differentiation incompletely defined
    • Whether NLRP1 vs. NLRP3 pathway dominance is tissue-specific remains unclear
  11. 2020 High

    Engineering of decoy-resistant IL-18 (DR-18) that evades IL-18BP blockade demonstrated that IL-18BP is the dominant barrier to IL-18 anti-tumor activity, and that enteric neuron-derived IL-18 is the non-redundant source for intestinal goblet cell antimicrobial defense, revealing cell-type-specific IL-18 sourcing.

    Evidence Directed evolution of DR-18 with tumor models and CD8+ T cell subset analysis; cell-type-specific conditional IL-18 KO mice (neuron, immune, epithelial) with Salmonella infection and scRNA-seq

    PMID:31923399 PMID:32581358

    Open questions at the time
    • Mechanism of IL-18 release from enteric neurons not defined
    • DR-18 clinical translation and potential toxicities not evaluated
  12. 2021 High

    Cryo-EM structure of the GSDMD pore revealed that electrostatic charge filtering selectively permits passage of mature (positively charged) IL-18 over the negatively charged precursor, establishing the physical mechanism of IL-18 release.

    Evidence Cryo-EM of GSDMD pore/prepore, liposome permeabilization with charge-variant IL-18 species, GSDMD acidic-residue mutagenesis

    PMID:33883744

    Open questions at the time
    • In vivo quantitative contribution of GSDMD pore vs. other release mechanisms not determined
    • Whether GSDMD selectivity operates identically across cell types not tested
  13. 2023 High

    Crystal structure of the caspase-4/pro-IL-18 complex uncovered a binary substrate-recognition mechanism—catalytic-site tetrapeptide engagement plus a unique exosite—explaining why human caspase-4/5 but not mouse caspase-11 can process pro-IL-18, and revealed autoinhibitory intramolecular interactions in the precursor that are relieved upon cleavage to generate IL-18Rα binding sites.

    Evidence Crystal structure, in vitro cleavage reconstitution, exosite mutagenesis converting caspase-11 to gain IL-18 processing, bacterial infection models

    PMID:37993714

    Open questions at the time
    • Whether the exosite mechanism operates similarly for caspase-1 in vivo not directly shown
    • Structural basis for caspase-5 processing not independently crystallized
  14. 2024 Medium

    Identification of tumor-specific IL-18 alternative splicing (ΔIL-18) driven by PTBP3 recruitment via H3K36me3-MRG15, with ΔIL-18 promoting immune evasion by stabilizing PD-1, and a parallel GFPT2-O-GlcNAcylation-YBX1 transcriptional axis promoting IL-18 secretion in pancreatic cancer, expanded understanding of IL-18 regulation in the tumor microenvironment.

    Evidence mRNA-seq, luciferase splicing reporters, antisense oligonucleotides, HuPBMC mouse models, Co-IP/MS for O-GlcNAcylated YBX1, ChIP for YBX1 on IL-18 promoter

    PMID:38575607 PMID:39116343

    Open questions at the time
    • ΔIL-18 splice isoform prevalence across cancer types not established
    • GFPT2-YBX1 axis not validated in non-pancreatic contexts
    • Independent replication of both findings pending
  15. 2025 High

    Discovery of a caspase-3-generated nuclear 15-kDa 'short IL-18' that activates a CDK8–STAT1 Ser727–ISG15 pathway to mobilize NK cell anti-tumor cytotoxicity independently of IL-18Rα established a second, receptor-independent effector arm for IL-18.

    Evidence Caspase-3 cleavage assay, subcellular fractionation/nuclear imaging, CDK8 inhibition, ISG15 ELISA, syngeneic tumor models with NK depletion, colorectal cancer patient tissue

    PMID:39891018

    Open questions at the time
    • Physiological contexts beyond cancer where short IL-18 operates are unknown
    • Whether short IL-18 nuclear translocation uses a defined import pathway not determined
    • Structural basis for CDK8-STAT1 activation by short IL-18 not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full ternary structure of the IL-18/IL-18Rα/IL-18Rβ signalosome, the relative quantitative contributions of different inflammasomes and caspases to IL-18 processing across tissues, the molecular mechanism of IL-18 release from enteric neurons, and the in vivo functional significance of the ΔIL-18 splice isoform.
  • Full ternary IL-18 signaling complex structure not solved
  • Tissue-specific inflammasome hierarchy for IL-18 processing not quantitatively established
  • Mechanism of IL-18 release from neurons undefined
  • In vivo relevance of ΔIL-18 splice variant awaits independent confirmation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 6 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 4 GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0005764 lysosome 1
Pathway
R-HSA-168256 Immune System 11 R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 5 R-HSA-5357801 Programmed Cell Death 4
Partners
CASP1CASP4GSDMDIL18BPIL18R1IL18RAPMYD88TICAM2

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 IL-18 (originally called IGIF) was cloned as a novel cytokine that induces IFN-γ production by T cells and enhances NK cell cytotoxicity; the gene encodes a 192-amino acid precursor protein with a mature form of 157 amino acids, with no homology to other known cytokines at the time. cDNA cloning, recombinant protein expression, IFN-γ induction assay in spleen cells, NK cytotoxicity assay Nature High 7477296
1996 Human IL-18 cDNA was cloned; recombinant human IL-18 induced IFN-γ production in mitogen-stimulated PBMC, enhanced NK cell cytotoxicity, augmented GM-CSF production, and decreased IL-10 production, establishing it as a pleiotropic cytokine designated IL-18. cDNA cloning from human liver library, recombinant protein expression in E. coli, PBMC stimulation assays, ELISA Journal of immunology High 8666798
1996 IL-18 (IGIF) synergizes with IL-12 to induce IFN-γ production from human T cells; IL-18 promotes T cell proliferation through an IL-2-dependent pathway and enhances Th1 cytokine production (IFN-γ, IL-2, GM-CSF) without affecting IL-4 or IL-10, demonstrating a distinct pathway from IL-12. Anti-CD3 stimulation of human T cells, ELISA, CTLL-2 bioassay, neutralizing antibodies European journal of immunology High 8766574
1997 Caspase-1 (ICE) cleaves the pro-IL-18 precursor at the authentic processing site with high efficiency, generating the active mature form; caspase-1-deficient Kupffer cells synthesized pro-IL-18 but failed to process it, and caspase-1-deficient mice showed diminished serum IFN-γ and IL-18 after LPS challenge. In vitro cleavage assay with recombinant ICE, ICE-knockout mice, LPS/P. acnes challenge model, ELISA Science High 8999548
1997 The human IL-18 receptor (IL-18Rα) was purified and identified as IL-1Rrp (IL-1 receptor-related protein); IL-18 binding to L428 cells had a Kd of ~18.5 nM with ~18,000 sites/cell; IL-18 binding was not competed by IL-1β; expression of IL-1Rrp cDNA in COS-1 cells conferred both IL-18 binding and signal transduction capacity. Radioligand binding assay, receptor purification by lectin and mAb chromatography, COS-1 cell expression system, N-terminal peptide sequencing The Journal of biological chemistry High 9325300
1997 IL-18 together with IL-12 induces IFN-γ production from activated B cells, which in turn inhibits IL-4-dependent IgE and IgG1 production and enhances IgG2a production; B cells from normal mice can become IFN-γ-producing cells in IFN-γ-deficient host mice in response to IL-12 plus IL-18. In vitro anti-CD40/IL-4 stimulation, ELISA, in vivo mouse models (N. brasiliensis, anti-IgD), adoptive transfer into IFN-γ KO mice Proceedings of the National Academy of Sciences High 9108085
1999 IL-18 can act as a potent co-inducer of IL-13 in NK and T cells when combined with IL-2 (independent of IFN-γ), demonstrating that IL-18 can promote Th2-type cytokine production in addition to its Th1-inducing activities, depending on the cytokine milieu. NK and T cell stimulation assays, ELISA, Northern blot, IFN-γ knockout mouse cells Journal of immunology High 10227975
1999 Bioactive (mature) IL-18 is predominantly present in Crohn's disease mucosa as an 18-kDa form, whereas in controls it exists as the 24-kDa precursor; active caspase-1 (ICE) p20 subunit is expressed in IBD samples, and antisense knockdown of IL-18 in CD LPMC reduced IFN-γ expression, placing IL-18 upstream of IFN-γ production in CD. Western blot, RT-PCR, antisense oligonucleotide knockdown, IFN-γ ELISA Journal of immunology Medium 10384110
2000 IL-18 signals through a receptor system (IL-18Rα and IL-18Rβ) analogous to the IL-1 receptor, activating the same downstream signal transduction pathway including NF-κB; IL-18-deficient mice have impaired NK cell activity and in vivo Th1 responses. IL-18 knockout mice, NK cytotoxicity assays, cytokine measurements Current opinion in immunology High 10679398
2000 IL-18 activates NF-κB and AP-1 in CD4+ T cells (Jurkat cells), driving IL-2 gene transcription and protein production; depletion of IL-18 from sarcoid epithelial lining fluid with neutralizing antibodies abrogated AP-1/NF-κB activation and IL-2 production, positioning IL-18 upstream of T cell IL-2 production. Transcription factor EMSA, luciferase/reporter assays, neutralizing antibody depletion, ELISA, Jurkat cell stimulation Journal of immunology Medium 11035116
2001 Human peripheral blood neutrophils constitutively express IL-18Rα and IL-18Rβ; IL-18 induces cytokine/chemokine release (protein synthesis-dependent), up-regulates CD11b, induces granule release, and enhances the respiratory burst after fMLP, but does not affect neutrophil apoptosis; IL-18 administration promoted neutrophil accumulation in vivo and IL-18 neutralization suppressed carrageenan-induced footpad inflammation. Flow cytometry, ELISA, myeloperoxidase assay, in vivo mouse models, neutralizing antibodies Journal of immunology High 11509635
2002 IL-18 expression in human atherosclerotic plaque occurs predominantly as the mature 18-kDa form in macrophages; endothelial cells, smooth muscle cells, and macrophages all constitutively express functional IL-18Rα/β complex; IL-18 signaling in these vascular cells induces IL-6, IL-8, ICAM-1, and MMP-1/-9/-13 expression, and IL-18 plus IL-12 induces IFN-γ in smooth muscle cells (but not endothelial cells). Immunohistochemistry, Western blot, in vitro cell stimulation, ELISA, RT-PCR The Journal of experimental medicine High 11805151
2002 IL-18 regulates IL-1β-dependent hepatic melanoma metastasis: B16 melanoma-conditioned medium stimulates hepatic sinusoidal endothelial cells to sequentially release TNF-α, IL-1β, and IL-18; exogenous IL-18 increases VCAM-1 expression on HSE and melanoma cell adhesion via a VCAM-1-dependent (not IL-1R or TNF-dependent) mechanism; anti-IL-18 or IL-18BP abolished this adhesion. In vitro co-culture adhesion assays, intrasplenic tumor injection model, IL-1β and caspase-1 KO mice, neutralizing antibodies, VCAM-1 blocking Proceedings of the National Academy of Sciences High 10639148
2002 ATP release from monocytes stimulated with microbial ligands or uric acid triggers autocrine P2X7 receptor activation, leading to K+ efflux and phospholipase A2 activation, which are required for caspase-1-dependent maturation and secretion of both IL-1β and IL-18; P2X7 antagonists or apyrase prevent IL-18 secretion. Primary human monocyte cultures, ATP measurement, P2X7 antagonists, apyrase treatment, caspase-1 inhibitors, ELISA, intracellular flow cytometry Proceedings of the National Academy of Sciences High 18523012
2003 IL-18 activates neutrophils via TNF-α induction, which drives production of leukotriene B4 (LTB4), causing neutrophil accumulation; IL-18-induced neutrophil recruitment and LTB4 production were blocked by LTB4 synthesis inhibitor MK-886, LTB4 receptor antagonist CP-105696, anti-TNF-α antibody, and was absent in TNFRp55-/- mice. In vivo peritoneal neutrophil recruitment model, LTB4 ELISA, pharmacological inhibitors, TNFRp55 knockout mice, anti-TNF-α neutralization Journal of immunology High 12847274
2003 Bcl6 functions as a sequence-specific transcriptional repressor of the IL-18 gene; a Bcl6-binding DNA sequence (IL-18BS) was identified upstream of exon 1 of the murine IL-18 gene and in the human IL-18 promoter; Bcl6 binding to IL-18BS was detected by gel retardation and ChIP assays and diminished after LPS stimulation; Bcl6 repressed IL-18 promoter-driven luciferase expression in an IL-18BS-dependent manner. Gel retardation (EMSA), chromatin immunoprecipitation (ChIP), luciferase reporter assay, dominant-negative transfection, Bcl6 KO macrophages, RT-PCR Journal of immunology High 12817026
2003 Langerhans cell-derived IL-18 contributes to contact hypersensitivity initiation; mature IL-18 (requiring caspase-1 cleavage) is necessary for IL-12-stimulated IFN-γ production by lymph node cells; caspase-1-/- LN cells showed impaired IFN-γ production that was restored by exogenous IL-18; CHS was significantly inhibited by neutralizing anti-IL-18 antibody and in caspase-1-/- mice. Murine CHS model, IL-18 neutralizing antibodies, caspase-1 KO mice, in vitro IFN-γ production assays, exogenous IL-18 rescue Journal of immunology High 11907086
2004 A highly stable human IL-18 protein was generated by replacing cysteines with serines based on the 3D crystal structure and receptor-binding mechanism, retaining full biological activity, establishing that the cysteine residues are not required for function but contribute to multimerization-based inactivation. Site-directed mutagenesis, recombinant protein production, biological activity assay (IFN-γ induction), structural analysis Biochemical and biophysical research communications Medium 15047165
2004 IL-18 directly induces maturation of myeloid dendritic cells (but not differentiation of monocytes): IL-18 stimulation increased CD83, HLA-DR, and co-stimulatory molecules on monocyte-derived DCs and KG-1 cells, decreased pinocytosis, and enhanced alloreactive T cell stimulatory capacity. Flow cytometry, pinocytosis assay, mixed lymphocyte reaction, monocyte-derived DC culture Cellular immunology Medium 15135292
2005 NK cells trigger immature DCs to polarize secretory lysosomes containing IL-18 toward the NK cell contact site in a Ca2+-dependent, tubulin-mediated manner; IL-18 is released at the synaptic cleft (not diffusely), activating only the interacting NK cell; this establishes a polarized secretion mechanism for the leaderless cytokine IL-18. Confocal microscopy, lysosome tracking, Ca2+ chelation, tubulin disruption, ELISA of synaptic vs. non-synaptic fractions Blood High 15802534
2007 IL-18 enhances IFN-γ-induced production of CXCL9, CXCL10, and CXCL11 in human keratinocytes by activating NF-κB, STAT1, and IRF-1 through PI3K/Akt and MEK/ERK pathways; antisense oligonucleotides against NF-κB p50/p65 or STAT1 suppressed chemokine production; IL-18 induced phosphorylation of ERK and Akt. Antisense oligonucleotides, ELISA, RT-PCR, kinase inhibitors (LY294002, SB203580, PD98059), Western blot for phospho-ERK and phospho-Akt, primary human keratinocyte cultures European journal of immunology High 17274000
2007 CD8+ T cell-derived granzyme B cleaves pro-IL-18 in keratinocytes to generate mature IL-18, functioning as an alternative IL-18 converting enzyme; GrB+ /caspase-1- CD8 T cells co-cultured with IFN-γ-treated HaCaT keratinocytes transferred GrB into HaCaT cells and increased mature IL-18 in culture supernatant. CD8+ T cell and HaCaT keratinocyte co-culture, ELISA for mature IL-18, flow cytometry for GrB, PCR for caspase-1 expression Archives of dermatological research Medium 23820889
2009 IL-18 downregulates collagen production in human dermal fibroblasts via ERK phosphorylation and Ets-1 transcription factor; siRNA-mediated Ets-1 knockdown blocked IL-18-regulated collagen expression; ERK inhibitor PD98059 blocked IL-18's inhibitory effect; IL-18 also inhibited TGF-β-induced collagen expression and reduced collagen in SSc fibroblasts. siRNA knockdown (Ets-1), ERK inhibitor (PD98059), Western blot (phospho-ERK), RT-PCR, ELISA, primary human dermal fibroblast cultures The Journal of investigative dermatology High 19865096
2009 IL-18 induces osteopontin (OPN) expression in cardiac fibroblasts via IRF-1 transcriptional regulation; blockade of IL-18 receptor with neutralizing antibody abolished OPN expression; IRF1 mutation or siRNA reduced IL-18 and OPN expression; IRF1-mutant mice showed reduced IL-18/OPN expression and less cardiac fibrosis with pressure overload. Cardiac fibroblast culture, IL-18R neutralizing antibody, IRF1 siRNA/mutation, mouse pressure overload model, echocardiography, Western blot, RT-PCR American journal of physiology. Heart and circulatory physiology High 19429811
2012 TRAM (TICAM-2) acts as a sorting adaptor for MyD88 in IL-18 signaling; a direct interaction between MyD88-TIR domain and TRAM was demonstrated in vitro; TRAM-deficient mice and RNAi experiments showed reduced IL-18 signal transduction; live cell imaging showed co-localized accumulation of MyD88 and TRAM at membrane regions; TRAM binding sites on MyD88 overlap with those for Mal/TIRAP. In vitro protein interaction assay, RNAi knockdown, TRAM-deficient mice, live cell imaging (co-localization), cell-based IL-18 signaling assays PloS one High 22685567
2013 Inflammasomes activate caspase-1, which processes pro-IL-18 (and pro-IL-1β) to their mature active forms; NLRP3 and other NLR inflammasomes serve as the upstream activating platforms for caspase-1-dependent IL-18 maturation. Inflammasome reconstitution, caspase-1 activity assays, IL-18 maturation assays, NLR overexpression/knockout systems Nature reviews. Immunology High 23702978
2014 The crystal structure of IL-18 bound to the ectodomain of IL-18Rα was determined; surface charge complementarity determines ligand-binding specificity of primary receptors in the IL-1 receptor family; the IL-18 signaling complex adopts an architecture similar to other agonistic IL-1 family cytokines. X-ray crystallography, structural analysis, binding site mapping FEBS letters High 25261253
2015 The NLRP1 inflammasome is the specific inflammasome that activates IL-18 to prevent obesity and metabolic syndrome; NLRP1-deficient mice phenocopy IL-18-deficient mice with spontaneous obesity; mice with activating NLRP1 mutations have elevated IL-18, decreased adiposity, and are resistant to diet-induced metabolic dysfunction; HFD-induced fatal cachexia in NLRP1-activating mutant mice was prevented by IL-18 genetic deletion. NLRP1 and IL-18 knockout mice, NLRP1 activating-mutation knock-in mice, IL-18 ELISA, body composition analysis, high-fat/high-protein diet challenges, genetic rescue (IL-18 deletion) Cell metabolism High 26603191
2015 IL-18 inhibits goblet cell maturation in intestinal epithelial cells by regulating the transcriptional program instructing goblet cell development; deletion of IL-18 or IL-18R1 in intestinal epithelial cells conferred protection from colitis; deletion of IL-18BP caused severe colitis with goblet cell loss that was rescued in IL-18BP-/-;IL-18rΔ/EC double mice, demonstrating the effect is mediated at the level of epithelial IL-18 signaling. Conditional epithelial cell-specific IL-18R1 and IL-18BP knockout mice, RNA-seq transcriptional analysis, histology, genetic epistasis (double knockout rescue) Cell High 26638073
2015 NK cells require IL-18 signaling (via MyD88, but not IL-1R) for robust primary expansion during MCMV infection but not for memory cell maintenance or recall responses; IL-12/STAT4 signaling in activated NK cells upregulates MyD88 expression, which then mediates IL-18 downstream signaling. MCMV infection model, IL-18R-/-, MyD88-/-, IL-1R-/- mice, STAT4-/- mice, adoptive transfer, flow cytometry Journal of immunology High 25589075
2016 IL-18 promotes neonatal sepsis lethality via IL-1R1 signaling (not adaptive immunity); IL-18 increases IL-17A production by intestinal γδT cells and Ly6G+ myeloid cells; blocking IL-17A reduced IL-18-potentiated mortality, defining an IL-18→IL-1R1→IL-17A lethal axis in neonatal sepsis. IL-18-null neonatal mice, IL-1R1 KO mice, IL-18 replenishment, anti-IL-17A blockade, genome-wide mRNA analysis of human neonatal sepsis samples, flow cytometry Proceedings of the National Academy of Sciences High 27114524
2018 Inflammasome-dependent activation of IL-18 (but not IL-1β) within the myocardium upon β1-AR/ROS signaling is the critical upstream regulator for chemokine expression, macrophage infiltration, and cardiac fibrosis; genetic deletion of IL-18 or NLRP3 attenuated chemokine expression and macrophage infiltration; IL-18 neutralizing antibodies selectively blocked chemokines and proinflammatory cytokines but not growth factors. Isoproterenol-induced β-AR stimulation model, IL-18 KO and NLRP3 KO mice, cytokine array, IL-18 neutralizing antibodies, cardiac histology European heart journal High 28549109
2020 IL-18BP is upregulated in diverse human and mouse tumors and limits IL-18 anti-tumor activity; 'decoy-resistant' IL-18 (DR-18) engineered by directed evolution is impervious to IL-18BP inhibition while maintaining signaling; DR-18 promoted poly-functional CD8+ T cells, reduced TOX+ exhausted CD8+ T cells, expanded TCF1+ stem-like CD8+ T cells, and enhanced NK cell maturation. Directed protein evolution, tumor mouse models, flow cytometry (CD8+ T cell subset analysis), IL-18BP neutralization, anti-PD-1 resistant tumor models Nature High 32581358
2020 Enteric neurons are the essential non-redundant source of IL-18 required for homeostatic antimicrobial protein (AMP) production by goblet cells; deletion of IL-18 specifically from enteric neurons (not immune or epithelial cells) rendered mice susceptible to invasive Salmonella infection; enteric neuronal IL-18 is specifically required for goblet cell AMP production as established by RNA-seq and single-cell sequencing. Cell type-specific conditional IL-18 knockout mice (neurons vs. immune vs. epithelial), Salmonella infection model, confocal microscopy, smFISH, RNA-seq, single-cell RNA-seq Cell High 31923399
2021 GSDMD activation in intestinal epithelial cells (but not immune cells) promotes IL-18 release (without affecting IL-18 transcript or maturation levels) to mediate goblet cell loss and colitis development; commensal E. coli overgrowth during colitis mediates GSDMD activation; Gsdmd-deficient mice had reduced colitis severity. DSS colitis model, Gsdmd KO mice, cell-type specific reconstitution, IL-18 ELISA (protein vs. transcript), 16S microbiome analysis, E. coli colonization experiments Frontiers in immunology High 34721422
2021 GSDMD pore structure establishes electrostatic filtering of cargo release: the GSDMD pore conduit is predominantly negatively charged, while IL-18 precursor has an acidic domain removed by caspase-1 cleavage; mature (positively charged) IL-18 passes through GSDMD pores faster than negatively charged precursor; mutation of GSDMD acidic residues compromised this selectivity. Cryo-EM structure of GSDMD pore and prepore, liposome permeabilization assay, mutagenesis, macrophage IL-18 secretion assay Nature High 33883744
2023 Human caspase-4 (but not mouse caspase-11) directly and efficiently processes pro-IL-18 at the same tetrapeptide site as caspase-1; the crystal structure of the caspase-4/pro-IL-18 complex reveals a binary substrate-recognition mechanism: the catalytic pocket engages the tetrapeptide, and a unique exosite (also used by caspase-1 and -5) recognizes a structure formed jointly by the propeptide and post-cleavage-site sequences; caspase-11 cannot target pro-IL-18 due to a structural deviation at the exosite; pro-IL-18 has autoinhibitory interactions between the propeptide and post-cleavage-site region; caspase cleavage induces conformational changes generating two critical IL-18Rα receptor-binding sites. Crystal structure (caspase-4/pro-IL-18 complex), in vitro cleavage assay, bacterial infection models, exosite mutagenesis (caspase-11 to restore IL-18 processing), IL-18Rα binding assays Nature High 37993714
2024 The GFPT2-O-GlcNAcylation-YBX1 axis promotes IL-18 secretion in pancreatic cancer cells: GFPT2-mediated O-GlcNAcylation causes YBX1 nuclear translocation, where YBX1 functions as a transcription factor to promote IL-18 transcription; confirmed by Co-IP and protein mass spectrometry identifying O-GlcNAcylated YBX1. Co-IP, protein mass spectrometry, cellular proteomics, transcription factor ChIP/reporter, YBX1 knockdown/overexpression Cell death & disease Medium 38575607
2024 PTBP3 promotes IL-18 exon skipping to generate a tumor-specific isoform ΔIL-18; H3K36me3 couples IL-18 transcription and alternative splicing by recruiting PTBP3 via MRG15; SETD2 (H3K36 methyltransferase) binds hnRNPL to interfere with PTBP3 binding to IL-18 pre-mRNA; ΔIL-18 promotes immune escape by reducing FBXO38-mediated PD-1 ubiquitin degradation in CD8+ T cells. mRNA-seq/GEO analysis, multi-omics, luciferase reporter for splicing, antisense oligonucleotides, HuPBMC mouse model, SETD2/PTBP3/MRG15 interaction assays, PD-1 ubiquitination assays Advanced science Medium 39116343
2025 Caspase-3 cleavage of IL-18 in cancer cells generates a 15-kDa 'short IL-18' form that is distinct from mature IL-18: short IL-18 is not secreted and does not bind IL-18Rα; instead it translocates to the nucleus, facilitating STAT1 Ser727 phosphorylation via CDK8, and enhancing ISG15 expression and secretion; this cascade mobilizes NK cells with increased cytotoxicity to eliminate syngeneic tumors. Caspase-3 cleavage assay, subcellular fractionation, IL-18Rα binding assay, nuclear translocation imaging, CDK8 inhibition, ISG15 ELISA, syngeneic tumor models, NK cell depletion, colorectal cancer patient tissue analysis Nature immunology High 39891018

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
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2000 Role of IL-18 in CD4+ T lymphocyte activation in sarcoidosis. Journal of immunology (Baltimore, Md. : 1950) 77 11035116
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2021 Dysregulated Microbiota-Driven Gasdermin D Activation Promotes Colitis Development by Mediating IL-18 Release. Frontiers in immunology 54 34721422
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2017 IL-18 Contributes to Bone Cancer Pain by Regulating Glia Cells and Neuron Interaction. The journal of pain 48 29079540
2020 The Inflammasome Signaling Proteins ASC and IL-18 as Biomarkers of Psoriasis. Frontiers in pharmacology 45 32903782
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2009 IL-18 downregulates collagen production in human dermal fibroblasts via the ERK pathway. The Journal of investigative dermatology 42 19865096
2003 Bcl6 is a transcriptional repressor for the IL-18 gene. Journal of immunology (Baltimore, Md. : 1950) 41 12817026
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2012 TRAM is involved in IL-18 signaling and functions as a sorting adaptor for MyD88. PloS one 30 22685567
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2015 In vivo and systems biology studies implicate IL-18 as a central mediator in chronic pain. Journal of neuroimmunology 28 26004155
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2005 Application of plasmid DNA encoding IL-18 diminishes development of herpetic stromal keratitis by antiangiogenic effects. Journal of immunology (Baltimore, Md. : 1950) 27 15972686
2007 Protection of CD8+ T cells from activation-induced cell death by IL-18. Journal of leukocyte biology 26 17400610
2005 IL-18 enhances SCF production of melanoma cells by regulating ROI and p38 MAPK activity. Immunology letters 26 15585325
2001 Regulation of IL-18 expression in virus infection. Scandinavian journal of immunology 25 11422901
2021 Machine learning implicates the IL-18 signaling axis in severe asthma. JCI insight 24 34591794
2018 Role of IL-18 in transplant biology. European cytokine network 24 30078783
2017 Leptin promotes IL‑18 secretion by activating the NLRP3 inflammasome in RAW 264.7 cells. Molecular medicine reports 24 29039567
2008 Functional IL-18 promoter gene polymorphisms in Tunisian nasopharyngeal carcinoma patients. Cytokine 24 18555694
2004 Generation of highly stable IL-18 based on a ligand-receptor complex structure. Biochemical and biophysical research communications 24 15047165
2024 PTBP3 Mediates IL-18 Exon Skipping to Promote Immune Escape in Gallbladder Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 23 39116343
2012 Reno-protective effect of NECA in diabetic nephropathy: implication of IL-18 and ICAM-1. European cytokine network 23 22995127
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2024 IL-18 and IL-18BP: A Unique Dyad in Health and Disease. International journal of molecular sciences 22 39769266
2019 Intestinal overexpression of IL-18 promotes eosinophils-mediated allergic disorders. Immunology 22 30779114
2013 IL-18 induces profibrotic renal tubular cell injury via STAT3 activation. American journal of physiology. Renal physiology 22 23904224
2004 Induction of dendritic cell maturation by IL-18. Cellular immunology 22 15135292
2002 IL-18 production in human pulmonary and pleural tuberculosis. Scandinavian journal of immunology 22 12472673
2025 Short IL-18 generated by caspase-3 cleavage mobilizes NK cells to suppress tumor growth. Nature immunology 21 39891018