Affinage

IL18

Interleukin-18 · UniProt Q14116

Length
193 aa
Mass
22.3 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 33 steps
  1. 1998 Medium

    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

    PMID:9638361

    Open questions at the time
    • Synthesized within a review rather than a single primary dataset
    • Does not define the receptor signaling branch driving IFN-γ
  2. 1999 High

    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

    PMID:9893178

    Open questions at the time
    • Did not resolve the structural basis of propeptide autoinhibition
    • NF-κB assignment later refined to p38 MAPK in epithelial contexts
  3. 2001 High

    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

    PMID:11145885

    Open questions at the time
    • Did not address in vivo regulation of IL-18BP abundance
    • Structural basis of the IL-18:IL-18BP interface not resolved
  4. 2001 Medium

    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

    PMID:11739524

    Open questions at the time
    • Did not establish the in vivo physiological consequence of the feedback
    • Mechanism of butyrate modulation undefined
  5. 2001 Medium

    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

    PMID:11509635

    Open questions at the time
    • Did not define downstream signaling in neutrophils
    • Effector mediators of recruitment unresolved until later work
  6. 2002 Medium

    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

    PMID:11907086

    Open questions at the time
    • Did not define the receptor signaling branch in this setting
    • Cellular target of IL-18 in the lymph node not pinpointed
  7. 2003 High

    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

    PMID:12817026

    Open questions at the time
    • Post-stimulation modification of Bcl6 not molecularly defined
    • Did not connect to type I IFN co-regulation later identified
  8. 2003 Medium

    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

    PMID:12847274

    Open questions at the time
    • Cell source of TNF-α in the cascade not pinned
    • Intracellular signaling linking IL-18R to LTB4 synthesis undefined
  9. 2004 High

    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

    PMID:15161979

    Open questions at the time
    • Context dependence of NF-κB vs p38 across cell types not resolved
    • Used a transfected epithelial system
  10. 2006 Medium

    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

    PMID:16785519

    Open questions at the time
    • Direct vs indirect induction of dendritic-cell OX40L not separated
    • Receptor signaling pathway in this context unmapped
  11. 2006 Medium

    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

    PMID:17052916

    Open questions at the time
    • Single in vitro method
    • Molecular basis of IL-18/IL-15 synergy undefined
  12. 2006 Medium

    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

    PMID:16493047

    Open questions at the time
    • Molecular link between IL-18 signaling and nucleotide excision repair unresolved
    • Receptor dependence not directly tested
  13. 2009 Medium

    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

    PMID:19429811 PMID:19865096

    Open questions at the time
    • Determinants of opposing fibroblast responses across tissues unexplained
    • Single-lab mechanisms per tissue
  14. 2011 Medium

    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

    PMID:21724589

    Open questions at the time
    • Mechanism of PD-1 upregulation by IL-18 undefined
    • Context distinguishing pro- vs antitumor IL-18 not resolved
  15. 2012 High

    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

    PMID:24084736

    Open questions at the time
    • Cellular source of pathogenic IL-18 in CAPS not defined
    • Residual pyroptotic pathway not molecularly dissected
  16. 2013 Medium

    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

    PMID:23028835

    Open questions at the time
    • Molecular basis of differential licensing unresolved
    • Single stimulus/cell type
  17. 2013 Medium

    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

    PMID:23820889

    Open questions at the time
    • Cleavage site for granzyme B not mapped
    • In vivo relevance not established
  18. 2013 Medium

    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

    PMID:23904224

    Open questions at the time
    • Link between IL-18R and STAT3 activation undefined
    • Single lab
  19. 2015 High

    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

    PMID:26638073

    Open questions at the time
    • Transcription factors mediating goblet-cell repression not fully defined
    • Source of pathogenic IL-18 in colitis left open
  20. 2015 High

    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

    PMID:26603191

    Open questions at the time
    • Target tissue and receptor signaling for metabolic effect undefined
    • Mechanism of cachexia unresolved
  21. 2016 Medium

    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

    PMID:27114524

    Open questions at the time
    • Mechanistic link between IL-18 and IL-17A induction undefined
    • Cell-intrinsic vs systemic effects not separated
  22. 2017 Medium

    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

    PMID:28468974

    Open questions at the time
    • Transcription factors integrating TLR and IFN signals not defined
    • Single lab
  23. 2017 Medium

    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

    PMID:28842466

    Open questions at the time
    • Receptor proximal events to p65 activation in ILC3s undefined
    • Single lab
  24. 2018 Medium

    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

    PMID:28549109 PMID:33181835

    Open questions at the time
    • Signaling pathway from IL-18R to ion channel downregulation undefined
    • Cell source of cardiac IL-18 not fully resolved
  25. 2018 Medium

    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

    PMID:29295842

    Open questions at the time
    • Cellular IFN-γ source downstream of IL-18 not identified
    • Single trigger model
  26. 2019 Medium

    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

    PMID:30982734

    Open questions at the time
    • Direct coupling of mitochondrial state to IL-18 maturation not resolved
    • Single lab
  27. 2020 High

    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

    PMID:32581358

    Open questions at the time
    • Long-term safety/autoinflammation of unopposed signaling not addressed
    • Receptor signaling differences from native IL-18 not detailed
  28. 2020 Medium

    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

    PMID:31710506

    Open questions at the time
    • Transcriptional integrators of TLR and IFN signals undefined
    • Patient data limited
  29. 2020 High

    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

    PMID:31923399

    Open questions at the time
    • Processing and secretion route of neuronal IL-18 undefined
    • Receptor signaling driving AMP program not mapped
  30. 2023 High

    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

    PMID:37993714

    Open questions at the time
    • Species difference between human caspase-4 and mouse caspase-11 not fully explained mechanistically
    • Structure of mature IL-18:receptor complex not determined here
  31. 2024 Medium

    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

    PMID:38575607

    Open questions at the time
    • Direct YBX1 binding to the IL-18 promoter not fully mapped
    • In vivo significance limited
  32. 2024 Medium

    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

    PMID:38906145

    Open questions at the time
    • Receptor-proximal coupling of IL-18R to SLC12A3 activation undefined
    • Complex multi-cell system
  33. 2025 High

    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

    PMID:39891018

    Open questions at the time
    • How short IL-18 enters the nucleus and engages CDK8 mechanistically undefined
    • Physiological triggers of caspase-3 cleavage versus inflammasome cleavage unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 2
Localization
GO:0005576 extracellular region 2 GO:0005634 nucleus 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-1643685 Disease 3 R-HSA-162582 Signal Transduction 2
Partners
CASP1CASP4GZMBIL18BPIL18R1IL18RAPIRAKTRAF6
Complex memberships
IL-18Rα/IL-18Rβ receptor complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 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. Crystal structure of caspase-4–pro-IL-18 complex; in vitro cleavage assays; mutagenesis of exosite; bacterial infection cell models Nature High 37993714
1999 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. In vitro caspase-1 cleavage assay; structural comparison; functional IFN-γ induction assays The Journal of allergy and clinical immunology High 9893178
1999 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. Receptor subunit identification; signal transduction pathway mapping by biochemical assays The Journal of allergy and clinical immunology High 9893178
1998 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. Receptor expression analysis; cytokine stimulation assays; T cell and NK cell functional assays Current opinion in immunology Medium 9638361
2004 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. Stable transfection of IL-18Rβ; p38 MAPK phosphorylation assay; NF-κB reporter assay; specific kinase inhibitors; COX-2 mRNA and PGE2 measurements Proceedings of the National Academy of Sciences of the United States of America High 15161979
2025 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. Caspase-3 cleavage assays; nuclear fractionation; IL-18Rα binding assays; CDK8 interaction studies; STAT1 phosphorylation analysis; syngeneic tumor models; mouse genetics Nature immunology High 39891018
2003 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. Gel retardation (EMSA); chromatin immunoprecipitation (ChIP); luciferase reporter assay; dominant-negative Bcl6 transfection; Bcl6-/- macrophages Journal of immunology (Baltimore, Md. : 1950) High 12817026
2017 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. TLR stimulation of macrophages; IFN signaling-deficient macrophages; cytokine mRNA and protein measurement; chronic vs. acute TLR stimulation Journal of immunology (Baltimore, Md. : 1950) Medium 28468974
2020 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. Primary human monocyte stimulation; JAK/STAT inhibitors; IFNβ neutralization; MAS mouse models; patient serum analysis American journal of respiratory and critical care medicine Medium 31710506
2015 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. Conditional knockout mice (Il18 ΔEC, Il18r1 ΔEC, Il18bp−/−); double-mutant epistasis; goblet cell transcriptional program analysis; DSS colitis model Cell High 26638073
2020 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. Cell-type-specific Il18 deletion; smFISH for IL-18 mRNA in neurons; RNA-seq and single-cell sequencing; bacterial infection model Cell High 31923399
2015 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. NLRP1 KO and activating-mutation knock-in mice; IL-18 KO rescue; high-fat diet metabolic phenotyping; genetic epistasis Cell metabolism High 26603191
2001 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. 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 of immunology (Baltimore, Md. : 1950) Medium 11509635
2003 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. 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 of immunology (Baltimore, Md. : 1950) Medium 12847274
2006 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. In vivo mouse immunization; CD134 blockade; IFN-γ−/− mice; NK cell depletion; IL-12 blockade; T cell clonal expansion assays Journal of immunology (Baltimore, Md. : 1950) Medium 16785519
2013 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. NLRP3 inflammasome activation with Listeria p60; ROS inhibitors; caspase-11-deficient DCs; ELISA for IL-1β and IL-18 PloS one Medium 23028835
2012 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. CAPS mouse models bred onto Il18r-null and Il1r-null backgrounds; phenotypic and cytokine analyses; genetic epistasis The Journal of clinical investigation High 24084736
2001 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. Surface plasmon resonance (SPR/Biacore) affinity measurements; IFN-γ induction bioassay inhibition Virology High 11145885
2018 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. Cytokine array; IL-18−/− and NLRP3−/− mice; IL-18 neutralizing antibodies; isoproterenol model; histology for fibrosis and macrophage infiltration European heart journal Medium 28549109
2009 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. Recombinant IL-18 treatment of cardiac fibroblasts; IL-18R neutralizing antibody; IRF1 siRNA knockdown; IRF1-mutant mice; pressure/volume overload models; Western blot/qPCR American journal of physiology. Heart and circulatory physiology Medium 19429811
2013 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. IL-18 stimulation of HK-2 cells; STAT3 inhibitor S3I-201; Western blotting for p-STAT3; IL-18BP transgenic mice with ureteral obstruction American journal of physiology. Renal physiology Medium 23904224
2009 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. ERK phosphorylation assay; PD98059 ERK inhibitor; Ets-1 siRNA; collagen gene expression and protein measurement; primary dermal fibroblast and SSc fibroblast cultures The Journal of investigative dermatology Medium 19865096
2006 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). In vitro NK cell proliferation assay; NK cell line (excluding indirect signaling); IL-18 + IL-15 co-stimulation Cytokine Medium 17052916
2017 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. IL-18 stimulation of human ILC3s; NF-κB pathway analysis; p65 promoter binding (ChIP/reporter); in situ human tonsil immunostaining Journal of immunology (Baltimore, Md. : 1950) Medium 28842466
2013 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. 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 Archives of dermatological research Medium 23820889
2001 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. IFN-γ stimulation; IL-18BPa mRNA and protein measurement; functional IFN-γ production bioassay; sodium butyrate treatment; organ cultures from intestinal biopsies Journal of immunology (Baltimore, Md. : 1950) Medium 11739524
2024 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. Co-IP; protein mass spectrometry identifying YBX1 O-GlcNAcylation; transcriptional reporter assays; GFPT2 KO/knockdown; cellular proteomics Cell death & disease Medium 38575607
2024 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. Metabolic flux analysis; SLC12A3 inhibition/KO; STING KO; mitochondrial DNA measurement; cGAMP measurement; intestinal tolerance models Immunity Medium 38906145
2011 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. Tumor-derived IL-18 knockdown (RNAi); IL-18BP depletion; PD-1 expression analysis on NK cells; PD-1-deficient mice; metastasis models Cancer research Medium 21724589
2020 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. Directed evolution; IL-18BP binding assays; mouse tumor models; flow cytometry for T cell subsets; comparison with wild-type IL-18 Nature High 32581358
2016 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. IL-18−/− neonatal mice; IL-1R1 KO; γδT cell analysis; IL-17A blockade; genome-wide blood mRNA analysis from septic neonates Proceedings of the National Academy of Sciences of the United States of America Medium 27114524
2007 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. In situ hybridization; immunohistochemistry with cell-type markers (calbindin-D28k, aquaporin-2, vacuolar H+-ATPase); confocal microscopy; Western blot; PCR Kidney international Medium 17687255
2006 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. UV irradiation of mice; IL-18 injection; apoptosis and DNA damage immunohistochemistry; Xpa-KO mice; contact hypersensitivity readout Journal of immunology (Baltimore, Md. : 1950) Medium 16493047
2018 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. SCD humanized mouse model; IL-18BP treatment; patch-clamp recording of Ito; recombinant IL-18 in isolated hearts; NF-κB phosphorylation assay; echocardiography Blood Medium 33181835
2006 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. RT-PCR; ELISA; JNK inhibitor SP600125; phospho-JNK Western blot Biochemical and biophysical research communications Low 16650813
2018 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. IL-18BP-KO mice; TLR9/CpG stimulation; IL-18R blockade; IFN-γ blockade; serum cytokine and IFN-γ signature gene analysis Blood Medium 29295842
2002 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. Caspase-1-KO mice; exogenous IL-18 rescue; anti-IL-18 neutralizing antibody; CHS in vivo model; mRNA expression in LN cells Journal of immunology (Baltimore, Md. : 1950) Medium 11907086
2019 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. CTL1 inhibition/knockdown; choline kinase inhibitors; mitochondrial lipid profiling; AMPK activation assay; DRP1 mitochondrial recruitment; mitophagy assay; IL-18 ELISA Cell metabolism Medium 30982734

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Interleukin-18 and IL-18 binding protein. Frontiers in immunology 734 24115947
2008 IL-1, IL-18, and IL-33 families of cytokines. Immunological reviews 707 18613828
1999 IL-18: A TH1-inducing, proinflammatory cytokine and new member of the IL-1 family. The Journal of allergy and clinical immunology 661 9893178
2011 Inflammasome activation and IL-1β and IL-18 processing during infection. Trends in immunology 565 21333600
2015 Epithelial IL-18 Equilibrium Controls Barrier Function in Colitis. Cell 471 26638073
2017 Augmentation of Antitumor Immunity by Human and Mouse CAR T Cells Secreting IL-18. Cell reports 432 28954221
1998 Regulation of interferon-gamma production by IL-12 and IL-18. Current opinion in immunology 432 9638361
1999 Bioactive IL-18 expression is up-regulated in Crohn's disease. Journal of immunology (Baltimore, Md. : 1950) 336 10384110
2020 IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy. Nature 300 32581358
2011 IL-18 induces PD-1-dependent immunosuppression in cancer. Cancer research 292 21724589
2000 The role of IL-18 in innate immunity. Current opinion in immunology 272 10679398
2018 IL-18 cleavage triggers cardiac inflammation and fibrosis upon β-adrenergic insult. European heart journal 262 28549109
2001 A role for IL-18 in neutrophil activation. Journal of immunology (Baltimore, Md. : 1950) 246 11509635
1999 IL-18 is produced by articular chondrocytes and induces proinflammatory and catabolic responses. Journal of immunology (Baltimore, Md. : 1950) 215 9916738
2011 Role of the inflammasome, IL-1β, and IL-18 in bacterial infections. TheScientificWorldJournal 207 22125454
2004 Differences in signaling pathways by IL-1beta and IL-18. Proceedings of the National Academy of Sciences of the United States of America 200 15161979
2019 Choline Uptake and Metabolism Modulate Macrophage IL-1β and IL-18 Production. Cell metabolism 198 30982734
2013 Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies. The Journal of clinical investigation 194 24084736
2001 IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp. Cytokine 169 11145836
2001 IL-12 and IL-18 are increased and stimulate IFN-gamma production in sarcoid lungs. Journal of immunology (Baltimore, Md. : 1950) 152 11123348
2023 Recognition and maturation of IL-18 by caspase-4 noncanonical inflammasome. Nature 148 37993714
2015 IL-18 Production from the NLRP1 Inflammasome Prevents Obesity and Metabolic Syndrome. Cell metabolism 148 26603191
2020 Enteric Nervous System-Derived IL-18 Orchestrates Mucosal Barrier Immunity. Cell 143 31923399
2023 Biological and clinical roles of IL-18 in inflammatory diseases. Nature reviews. Rheumatology 132 38081945
2016 Interleukin 18 (IL-18) as a target for immune intervention. Acta biochimica Polonica 125 26885772
2004 Evidence for altered interleukin 18 (IL)-18 pathway in human heart failure. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 123 15371332
2013 IL-18 in inflammatory and autoimmune disease. Cellular and molecular life sciences : CMLS 119 23892891
2001 Expression and release of IL-18 binding protein in response to IFN-gamma. Journal of immunology (Baltimore, Md. : 1950) 114 11739524
2018 Unopposed IL-18 signaling leads to severe TLR9-induced macrophage activation syndrome in mice. Blood 112 29295842
2017 Cutting Edge: Distinct Regulatory Mechanisms Control Proinflammatory Cytokines IL-18 and IL-1β. Journal of immunology (Baltimore, Md. : 1950) 106 28468974
2018 Analysis of Serum Interleukin (IL)-1β and IL-18 in Systemic Lupus Erythematosus. Frontiers in immunology 105 29930551
2016 Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18. Proceedings of the National Academy of Sciences of the United States of America 97 27114524
2018 TNFα and IL-1β but not IL-18 Suppresses Hippocampal Long-Term Potentiation Directly at the Synapse. Neurochemical research 95 29619614
2009 IL-18 binding protein-expressing mesenchymal stem cells improve myocardial protection after ischemia or infarction. Proceedings of the National Academy of Sciences of the United States of America 91 19805173
2017 IL-18 Drives ILC3 Proliferation and Promotes IL-22 Production via NF-κB. Journal of immunology (Baltimore, Md. : 1950) 84 28842466
2012 Distinct licensing of IL-18 and IL-1β secretion in response to NLRP3 inflammasome activation. PloS one 84 23028835
2009 IL-18 neutralization ameliorates obstruction-induced epithelial-mesenchymal transition and renal fibrosis. Kidney international 84 19536084
2009 IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice. American journal of physiology. Heart and circulatory physiology 82 19429811
2003 IL-18 enhances collagen-induced arthritis by recruiting neutrophils via TNF-alpha and leukotriene B4. Journal of immunology (Baltimore, Md. : 1950) 81 12847274
2006 IL-18 bridges innate and adaptive immunity through IFN-gamma and the CD134 pathway. Journal of immunology (Baltimore, Md. : 1950) 80 16785519
2015 IL-18 and Cutaneous Inflammatory Diseases. International journal of molecular sciences 74 26690141
2001 Expression of IL-18 in psoriasis. Archives of dermatological research 72 11550806
2007 IL-18 is expressed in the intercalated cell of human kidney. Kidney international 64 17687255
2006 IL-18 acts synergistically with IL-15 in stimulating natural killer cell proliferation. Cytokine 64 17052916
2007 IL-15 mediates antigen-induced neutrophil migration by triggering IL-18 production. European journal of immunology 63 17979156
1999 Regulation of human IL-18 mRNA expression. Clinical immunology (Orlando, Fla.) 61 9884348
2022 GMP-Compliant Manufacturing of TRUCKs: CAR T Cells targeting GD2 and Releasing Inducible IL-18. Frontiers in immunology 60 35401506
2014 Inflammasome-dependent and -independent IL-18 production mediates immunity to the ISCOMATRIX adjuvant. Journal of immunology (Baltimore, Md. : 1950) 59 24610009
2001 Enhanced IL-18 expression in common skin tumors. Immunology letters 59 11600201
2006 IL-18 enhances thrombospondin-1 production in human gastric cancer via JNK pathway. Biochemical and biophysical research communications 55 16650813
2002 Contribution of Langerhans cell-derived IL-18 to contact hypersensitivity. Journal of immunology (Baltimore, Md. : 1950) 54 11907086
2020 Synergistic Signaling of TLR and IFNα/β Facilitates Escape of IL-18 Expression from Endotoxin Tolerance. American journal of respiratory and critical care medicine 51 31710506
2017 IL-18 Contributes to Bone Cancer Pain by Regulating Glia Cells and Neuron Interaction. The journal of pain 51 29079540
2001 Orthopoxvirus IL-18 binding proteins: affinities and antagonist activities. Virology 51 11145885
2010 Serum IL-18 and IL-18BP levels in patients with Chikungunya virus infection. Viral immunology 48 20121409
2015 Increased expression of IL-18 in the serum and islets of type 1 diabetics. Molecular immunology 47 25576800
2020 The Inflammasome Signaling Proteins ASC and IL-18 as Biomarkers of Psoriasis. Frontiers in pharmacology 46 32903782
2018 Inhibition of IL-18 reduces renal fibrosis after ischemia-reperfusion. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 44 30119258
2009 IL-18 downregulates collagen production in human dermal fibroblasts via the ERK pathway. The Journal of investigative dermatology 42 19865096
2006 IL-18 reduces ultraviolet radiation-induced DNA damage and thereby affects photoimmunosuppression. Journal of immunology (Baltimore, Md. : 1950) 41 16493047
2003 Bcl6 is a transcriptional repressor for the IL-18 gene. Journal of immunology (Baltimore, Md. : 1950) 41 12817026
2003 Pathophysiological roles for IL-18 in inflammatory arthritis. Expert opinion on therapeutic targets 41 14640907
2004 Role of IL-18 in pathogenesis of endometriosis. Human reproduction (Oxford, England) 40 14998974
2021 IL-18 mediates sickle cell cardiomyopathy and ventricular arrhythmias. Blood 39 33181835
2012 IL-27 Regulates IL-18 binding protein in skin resident cells. PloS one 37 22761702
2016 The role of IL-18 in type 1 diabetic nephropathy: The problem and future treatment. Cytokine 36 26836949
2009 IL-18 skews the invariant NKT-cell population via autoreactive activation in atopic eczema. European journal of immunology 36 19637196
2022 IL-18 deficiency ameliorates the progression from AKI to CKD. Cell death & disease 34 36379914
2001 IL-18 not required for IRBP peptide-induced EAU: studies in gene-deficient mice. Investigative ophthalmology & visual science 34 11133864
2019 Dual roles of IL-18 in colitis through regulation of the function and quantity of goblet cells. International journal of molecular medicine 32 31017261
2013 Clinical strategies for the blockade of IL-18 in inflammatory bowel diseases. Current drug targets 32 23651166
2013 CD8+ T cell granzyme B activates keratinocyte endogenous IL-18. Archives of dermatological research 32 23820889
2024 The GFPT2-O-GlcNAcylation-YBX1 axis promotes IL-18 secretion to regulate the tumor immune microenvironment in pancreatic cancer. Cell death & disease 31 38575607
2017 Interleukin (IL)-18, cooperatively with IL-23, induces prominent inflammation and enhances psoriasis-like epidermal hyperplasia. Archives of dermatological research 31 28299442
2020 Rapamycin Inhibited Pyroptosis and Reduced the Release of IL-1β and IL-18 in the Septic Response. BioMed research international 29 32851082
2025 Short IL-18 generated by caspase-3 cleavage mobilizes NK cells to suppress tumor growth. Nature immunology 26 39891018
2024 PTBP3 Mediates IL-18 Exon Skipping to Promote Immune Escape in Gallbladder Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 26 39116343
2024 IL-18 and IL-18BP: A Unique Dyad in Health and Disease. International journal of molecular sciences 26 39769266
2004 Therapeutic potential of targeting IL-1 and IL-18 in inflammation. Expert opinion on biological therapy 26 15174967
2021 Machine learning implicates the IL-18 signaling axis in severe asthma. JCI insight 25 34591794
2001 Regulation of IL-18 expression in virus infection. Scandinavian journal of immunology 25 11422901
2019 Intestinal overexpression of IL-18 promotes eosinophils-mediated allergic disorders. Immunology 24 30779114
2018 Role of IL-18 in transplant biology. European cytokine network 24 30078783
2016 IL-1β and IL-18 inhibition of HIV-1 replication in Jurkat cells and PBMCs. Biochemical and biophysical research communications 24 27049306
2008 Functional IL-18 promoter gene polymorphisms in Tunisian nasopharyngeal carcinoma patients. Cytokine 24 18555694
2007 Increased IL-18 production by dendritic cells in active inflammatory myopathies. Annals of the New York Academy of Sciences 23 17804546
2013 IL-18 induces profibrotic renal tubular cell injury via STAT3 activation. American journal of physiology. Renal physiology 22 23904224
2002 IL-18 production in human pulmonary and pleural tuberculosis. Scandinavian journal of immunology 22 12472673
2024 A metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance. Immunity 21 38906145
2022 Excessive IL-10 and IL-18 trigger hemophagocytic lymphohistiocytosis-like hyperinflammation and enhanced myelopoiesis. The Journal of allergy and clinical immunology 21 35792218
2019 Novel Immunoregulatory Functions of IL-18, an Accomplice of TGF-β1. Cancers 20 30641867
2011 IL-18 is required for self-reactive T cell expansion in NOD mice. Journal of autoimmunity 20 21414755
2023 IL-18 in Autoinflammatory Diseases: Focus on Adult Onset Still Disease and Macrophages Activation Syndrome. International journal of molecular sciences 19 37446301
2021 Genetic and commensal induction of IL-18 drive intestinal epithelial MHCII via IFNγ. Mucosal immunology 19 34103660
2019 LncRNA GAS5 overexpression downregulates IL-18 and induces the apoptosis of fibroblast-like synoviocytes. Clinical rheumatology 19 31372853
2011 VEGF and IL-18 in induced sputum of lung cancer patients. Cytokine 19 21398142
2010 Potential role of IL-18 in the immunopathogenesis of AIDS, HIV-associated lipodystrophy and related clinical conditions. Current HIV research 19 19954415
2005 Physiological role of IL-15 and IL-18 at the maternal-fetal interface. Chemical immunology and allergy 19 16129949
2021 IL-18 Promotes Erythrophagocytosis and Erythrocyte Degradation by M1 Macrophages in a Calcific Microenvironment. The Canadian journal of cardiology 18 33984428
2012 Immunotherapeutic applications of IL-18. Immunotherapy 18 23240755

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