Alternative titles; symbols
HGNC Approved Gene Symbol: IL18
Cytogenetic location: 11q23.1 Genomic coordinates (GRCh38): 11:112,143,260-112,164,094 (from NCBI)
Okamura et al. (1995) cloned an interferon-gamma (IFNG; 147570)-inducing factor that augments natural killer (NK) cell activity in spleen cells. The gene encodes a precursor protein of 192 amino acids and a mature protein of 157 amino acids. Messenger RNAs for the gene, designated IGIF by them, and for interleukin-12 (IL12; see 161560) were readily detected in Kupffer cells and activated macrophages. Recombinant IGIF induced IFNG more potently than did IL12, which is also a NK-cell stimulatory factor. Administration of anti-IGIF antibodies prevented liver damage in mice inoculated with Propionibacterium acnes and challenged with lipopolysaccharide that induces toxic shock. Okamura et al. (1995) speculated that IGIF may be involved in the development of Th1 cells and also in mechanisms of tissue injury in inflammatory reactions. The interferon-gamma-inducing factor is also known as interleukin-18 (Sarvetnick, 1997).
Sanchez et al. (2009) noted that the IL18 gene contains 6 exons.
By analysis of a human/rodent somatic cell hybrid panel and radiation hybrid analysis, Nolan et al. (1998) mapped the IL18 gene to 11q22.2-q22.3, close to the DRD2 (126450) gene.
The adhesion of circulating cancer cells to capillary endothelia is a critical step in the initiation of metastasis. Vidal-Vanaclocha et al. (2000) reported results demonstrating a role for interleukin-1-beta (IL1B; 147720) and IL18 in the development of hepatic metastases of melanoma in vivo. In vitro, soluble products from mouse melanoma cells stimulated hepatic sinusoidal endothelium to sequentially release tumor necrosis factor-alpha (TNFA; 191160), IL1B, and IL18. The IL18 cytokine increased expression of vascular cell adhesion molecule-1 (VCAM1; 192225) and the adherence of melanoma cells.
Shida et al. (2001) found that 30% of normal subjects had a detectable, functionally inactive IL18 fragment, which they termed IL18 type 2, bound to IgM in plasma. The level of IL18 type 2 was 10- to 100-fold higher than that of conventional, active IL18 type 1 in these subjects.
Using RT-PCR, immunoblot, and immunofluorescence microscopy analyses, Sugawara et al. (2001) demonstrated that oral epithelial cells express IL18 mRNA and the 24-kD IL18 precursor protein. ELISA analysis showed that stimulation of the cells with proteinase-3 (PRTN3; 177020) and lipopolysaccharide (LPS) after IFNG priming leads to intracellular production and secretion of the 18-kD bioactive form of IL18 in a caspase-1 (CASP1; 147678)-independent fashion. Cell fractionation and immunoblot analyses indicated that PRTN3 acts on the cell surface after the IFNG priming, not intracellularly. Sugawara et al. (2001) proposed that PRTN3 together with LPS and IFNG may be involved in mucosal inflammation, such as periodontitis.
Pizarro et al. (1999) detected increased IL18 mRNA and protein expression in intestinal epithelial cells and lamina propria mononuclear cells in Crohn disease tissue compared with ulcerative colitis (see 266600) and normal tissue.
By immunohistochemical analysis, Corbaz et al. (2002) showed that IL18-binding protein (IL18BP; 604113) expression in intestinal tissue is increased in endothelial cells as well as cells of the submucosa and overlying lymphoid aggregates in Crohn disease patients compared with controls. Immunofluorescent microscopy demonstrated colocalization with macrophage and endothelial cell markers, but not with those of lymphocytes or epithelial cells. Real-time PCR and ELISA analysis detected increased levels of both IL18 and IL18BP in the Crohn disease intestinal tissue. Unbound neutralizing isoforms a and c of IL18BP were in excess compared with IL18 in the Crohn disease patients, indicating that IL18BP upregulation correlates with increased IL18 expression in Crohn disease. Corbaz et al. (2002) suggested that despite the presence of IL18BP, which has been shown to ameliorate colitis in a mouse model (ten Hove et al., 2001), some IL18 activity may be available for perpetuating the pathogenesis of Crohn disease.
Henao-Mejia et al. (2012) demonstrated that NLRP6 (609650) and NLRP3 (606416) inflammasomes and the effector protein IL18 negatively regulate nonalcoholic fatty liver disease/nonalcoholic steatohepatitis progression, as well as multiple aspects of metabolic syndrome via modulation of the gut microbiota. Different mouse models revealed that inflammasome deficiency-associated changes in the configuration of the gut microbiota are associated with exacerbated hepatic steatosis and inflammation through influx of TLR4 (603030) and TLR9 (605474) agonists into the portal circulation, leading to enhanced hepatic TNFA expression, which drives NASH progression. Furthermore, cohousing of inflammasome-deficient mice with wildtype mice resulted in exacerbation of hepatic steatosis and obesity. Thus, Henao-Mejia et al. (2012) concluded that altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of multiple metabolic syndrome-associated abnormalities, highlighting the central role of the microbiota in the pathogenesis of theretofore seemingly unrelated systemic autoinflammatory and metabolic disorders.
Zhang et al. (2014) reported that treatment with bacterial flagellin prevented rotavirus (RV) infection in mice and cured chronically RV-infected mice. Protection was independent of adaptive immunity and interferon (see 147660) and required the flagellin receptors Tlr5 (603031) and Nlrc4 (606831). Flagellin-induced activation of Tlr5 on dendritic cells elicited production of the cytokine Il22 (605330), which induced a protective gene expression program in intestinal epithelial cells. Flagellin also induced Nlrc4-dependent production of Il18 and immediate elimination of RV-infected cells. Administration of Il22 and Il18 to mice fully recapitulated the capacity of flagellin to prevent or eliminate RV. Zhang et al. (2014) proposed activation of innate immunity with flagellin, IL22, or IL18 as a strategy to combat emerging and recalcitrant viral pathogens.
Zhou et al. (2020) showed that IL18BP, a high-affinity IL18 decoy receptor, is frequently upregulated in diverse human and mouse tumors and limits the antitumor activity of IL18 in mice. Using directed evolution, Zhou et al. (2020) engineered a 'decoy-resistant' IL18 that maintains signaling potential but is impervious to inhibition by IL18BP. Unlike wildtype IL18, decoy-resistant IL18 exerted potent antitumor effects in mouse tumor models by promoting the development of polyfunctional effector CD8+ T cells, decreasing the prevalence of exhausted CD8+ T cells that express the transcriptional regulator of exhaustion TOX (606863), and expanding the pool of stem-like TCF1 (HNF1A; 142410)+ precursor CD8+ T cells. Decoy-resistant IL18 also enhanced the activity and maturation of natural killer cells to effectively treat anti-PD1 (600244)-resistant tumors that have lost surface expression of major histocompatibility complex class I (see 142800) molecules. Zhou et al. (2020) concluded that their results highlighted the potential of the IL18 pathway for immunotherapeutic intervention and implicated IL18BP as a major therapeutic barrier.
Involvement in Coronary Artery Disease
Mallat et al. (2001) examined stable and unstable human carotid atherosclerotic plaques retrieved by endarterectomy for the presence of IL18 and found that IL18 was highly expressed in the atherosclerotic plaques compared to normal control arteries and was localized mainly in plaque macrophages. Significantly higher levels of IL18 mRNA were found in symptomatic (unstable) plaques than asymptomatic (stable) plaques. Mallat et al. (2001) suggested that IL18 plays a major role in atherosclerotic plaque destabilization leading to acute ischemic syndromes.
In a prospective study of 1,229 patients with documented coronary artery disease, Blankenberg et al. (2002) measured baseline serum concentrations of IL18 and other markers of inflammation. Median serum IL18 levels were significantly higher among patients who had a fatal cardiovascular event during the follow-up period (median, 3.9 years) than among those who did not. After adjustment for potential confounders, the relationship remained and was observed in both patients with stable angina and those with unstable angina at baseline. Blankenberg et al. (2002) concluded that serum IL18 is a strong independent predictor of death from cardiovascular causes in patients with coronary artery disease regardless of clinical status at admission.
Blankenberg et al. (2003) evaluated the relationship between baseline plasma levels of IL18 and the subsequent incidence of coronary events over a 5-year follow-up in healthy European men aged 50 to 59 years. Baseline levels of IL18 were significantly higher in 335 European men who had a coronary event than in 670 age-matched controls (p = 0.005). In all models, IL18 made an independent contribution to the prediction of risk over lipids or other inflammatory markers.
Francisella tularensis, the causative agent of tularemia and a potential biohazard threat, evades the immune response, including innate responses through the lipopolysaccharide receptor TLR4 (603030), thus increasing its virulence. Huang et al. (2010) deleted the bacterium's ripA gene and found that mouse macrophages and a human monocyte line produced significant amounts of the inflammatory cytokines TNF, IL18, and IL1B in response to the mutant. IL1B and IL18 secretion was dependent on PYCARD (606838) and CASP1, and MYD88 (602170) was required for inflammatory cytokine synthesis. A complemented strain with restored expression of ripA restored immune evasion, as well as activation of the MAP kinases ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948), JNK (see 601158), and p38 (MAPK14; 600289). Pharmacologic inhibition of these MAPKs reduced cytokine induction by the ripA deletion mutant. Mice infected with the mutant exhibited stronger Il1b and Tnfa responses than mice infected with the wildtype live vaccine strain. Huang et al. (2010) concluded that the F. tularensis ripA gene product functions by suppressing MAPK pathways and circumventing the inflammasome response.
Tiret et al. (2005) genotyped 22 polymorphisms of the IL18, IL18R1 (604494), IL18RAP (604509), and IL18BP (604113) genes in 1,288 patients with coronary artery disease who were followed for a median of 5.9 years. Baseline IL18 levels were predictive of cardiovascular deaths occurring within the first 4 years but not of later deaths. Haplotypes of the IL18 gene were associated with IL18 levels and cardiovascular mortality after adjustment for cardiovascular risk factors; adjustment for baseline IL18 levels abolished the association. Tiret et al. (2005) concluded that variations of the IL18 gene influence circulating levels of IL18 and clinical outcome in patients with coronary artery disease.
Associations Pending Confirmation
Lee et al. (2007) reported a significantly higher frequency of the 105A allele of the IL18 105A-C SNP in Chinese rheumatoid arthritis (RA; 180300) patients compared with controls. The relative risk of rheumatoid arthritis was stronger in 105A homozygotes.
Sanchez et al. (2009) selected 9 SNPs spanning the IL18 gene and genotyped an independent set of 752 Spanish systemic lupus erythematosus (SLE; 152700) patients and 595 Spanish controls. A -1297T-C SNP (rs360719) survived correction for multiple tests and was genotyped in 2 case-control replication cohorts from Italy and Argentina. Combined analysis for the risk C allele remained significant (pooled odds ratio = 1.37, 95% CI 1.21-1.54, corrected p = 1.16 x 10(-6)). There was a significant increase in the relative expression of IL18 mRNA in individuals carrying the risk -1297C allele; in addition, -1297C allele created a binding site for the transcriptional factor OCT1 (POU2F1; 164175). Sanchez et al. (2009) suggested that the rs360719 variant may play a role in susceptibility to SLE and in IL18 expression.
Rothe et al. (1997) concluded that IGIF expression is abnormally regulated in NOD mice and is closely associated with diabetes development. They showed that the Igif gene maps to mouse chromosome 9 within the Idd2 interval and is therefore a candidate for the Idd2 diabetes susceptibility gene.
Okamoto et al. (2000) showed that Il18 has a protective effect against the development of chronic graft-versus-host disease (GVHD; see 614395) in mouse. Using a murine bone marrow transplant (BMT) model, Reddy et al. (2001) showed that blockade of Il18 accelerated acute GVHD mortality. In contrast, Il18 administration reduced serum Tnf and lipopolysaccharide levels, decreased intestinal pathology, attenuated early donor T-cell expansion, increased Fas (TNFRSF6; 134637) expression and apoptosis in donor T cells, and enhanced survival. With Fas-deficient or Ifng knockout donor mice, Il18 did not protect BMT recipients from acute GVHD. Reddy et al. (2001) concluded that IL18 regulates acute GVHD by enhancing FAS-mediated apoptosis of donor T cells early after BMT in an IFNG-dependent manner.
In transgenic mice, Konishi et al. (2002) showed that IL18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesions independently of IgE/Stat6 (601512) under specific pathogen-free conditions. Overrelease of IL18 initiated atopic dermatitis-like inflammation, which was accelerated by interleukin 1-alpha (IL1A; 147760).
The lupus-like autoimmune syndrome of mice (lpr) is characterized by progressive lymphadenopathy and autoantibody production, leading to early death from renal failure. Activation of T helper lymphocytes is one of the events in the pathogenesis of the disease in these mice and likely in human systemic lupus erythematosus (SLE; 152700). Among T helper lymphocyte-dependent cytokines, interferon-gamma plays a pivotal role in the abnormal cell activation and the fatal development of the lpr disease. IL18, an inducer of IFN-gamma in T lymphocytes and NK cells, may contribute to the disease because cells from lpr mice are hypersensitive to Il18 and express high levels of Il18. To assess the contribution of Il18 to the pathogenesis in the animal model, Bossu et al. (2003) attempted in vivo inhibition of Il18. Young lpr mice were vaccinated against autologous Il18 by repeated administration of a cDNA coding for the murine Il18 precursor. Vaccinated mice produced autoantibodies to murine Il18 and exhibited a significant reduction in spontaneous lymphoproliferation and IFN-gamma production as well as less glomerulonephritis and renal damage. Moreover, mortality was significantly delayed in anti-Il18-vaccinated mice. Bossu et al. (2003) concluded that Il18 plays a major role in the pathogenesis of the autoimmune syndrome of lpr mice and that a reduction in IL18 activity could be a therapeutic strategy in autoimmune diseases.
Van Der Sluijs et al. (2005) found that Il18 -/- mice recovered from influenza virus infection with a lower viral load in lungs and a greater gain in body weight compared with wildtype mice. No differences could be detected in Ifng levels, but Il18 -/- mice had significantly reduced Tnf and Mcp1 (CCL2; 158105). There were no differences in mortality between wildtype and Il18 -/- mice following challenge with a lethal dose of influenza. Van Der Sluijs et al. (2005) concluded that IL18 is upregulated in lung after influenza infection and that IL18 deficiency is associated with accelerated viral clearance and enhanced activation of CD4 (186940)-positive T cells.
Netea et al. (2006) noted that, in contrast to other proinflammatory cytokines, there is a constitutive intracellular pool of pro-IL18. After cleavage of pro-IL18 by CASP1, IL18 bioactivity is kept in balance by high concentrations of IL18BP in blood and tissues. IL18 concentrations are increased in individuals with type 2 IDDM (125852), obesity, or polycystic ovary syndrome (see 184700). Netea et al. (2006) found that mice deficient in Il18 had markedly increased body weight compared with wildtype littermates after 3 months of age and displayed obesity, insulin resistance, hyperglycemia, lipid abnormalities, and atherosclerosis. The weight gain was associated with significantly increased body fat, food intake, glucose, insulin, glucagon, cholesterol, and leptin (LEP; 164160). Histologic analysis of various organs showed only increased size of pancreatic islets in mutant mice. Leptin administration or intracerebral, but not intravenous, administration of recombinant Il18 reduced food intake. Intraperitoneal administration of recombinant Il18 restored insulin sensitivity and corrected hyperglycemia through activation of Stat3 (102582) phosphorylation in Il18 -/- mice. Il18r -/- and Il18bp transgenic mice had phenotypes similar to that of Il18 -/- mice. Netea et al. (2006) concluded that IL18 has an important role in homeostasis of energy intake and insulin sensitivity.
Nowarski et al. (2015) found that deletion of Il18 or Il18r1 in mouse intestinal epithelial cells protected mice from dextran sodium sulfate (DSS)-induced colitis and mucosal damage. In contrast, deletion of Il18bp, a negative regulator of Il18, resulted in severe colitis associated with loss of mature goblet cells. Il18bp -/- mice could be rescued from colitis and goblet-cell loss by deletion of Il18r1 in epithelial cells. Administering Il18 along with DSS to wildtype mice inhibited goblet-cell maturation, which preceded disease manifestation. Nowarski et al. (2015) concluded that IL18 signaling in intestinal epithelial cells controls colitis severity.
Wynn et al. (2016) found that Il18 -/- neonatal mice were highly protected from polymicrobial sepsis, whereas replenishment of Il18 increased lethality to sepsis or endotoxemia. Increased lethality depended on increased Il1r1 (147810) signaling, but not adaptive immunity. Transcriptomic analysis of human neonates with sepsis revealed elevated levels of IL18, IL18R1, and IL18RAP, and pathway analysis identified a role for IL17R (IL17RA; 605461). In mice, plasma Il17a (603149) produced by lamina propria and lung parenchyma cells was significantly amplified following exposure to Il18 and sepsis. Anti-Il17ra blockade or deletion of Il17a ablated the deleterious effects of Il18 on sepsis mortality in mice. Wynn et al. (2016) concluded that IL17A is an effector of IL18-mediated injury in neonatal sepsis and proposed that disruption of the tissue-destructive IL18-IL1-IL17A axis may be a therapeutic approach to improve outcomes in neonatal sepsis.
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