Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: IL18BP
Cytogenetic location: 11q13.4 Genomic coordinates (GRCh38) : 11:71,998,909-72,008,200 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.4 | {?Hepatitis, fulminant viral, susceptibility to} | 618549 | Autosomal recessive | 3 |
Interleukin-18 (IL18; 600953) is a pleiotropic cytokine whose excessive production may contribute to chronic inflammatory conditions and exacerbate certain disease states. Aizawa et al. (1999) hypothesized that an IL18 regulatory factor may neutralize the effects of high IL18 levels. In studies to detect and characterize this factor, they identified and purified mouse Il18-binding protein (Il18bp) and cloned mouse Il18bp cDNAs. Using the mouse Il18bp cDNAs, Aizawa et al. (1999) isolated human IL18BP cDNAs from a liver cDNA library. The human cDNA sequence encodes a predicted 194-amino acid protein containing a 30-amino acid signal peptide and 4 potential N-glycosylation sites but no transmembrane domains. Human and mouse IL18BP share 60.8% amino acid similarity. Northern blot analysis of human tissues detected a 1.6-kb IL18BP transcript that was expressed strongly in heart, lung, and placenta.
Independently, Novick et al. (1999) isolated IL18BP by affinity chromatography from human urine. SDS-PAGE analysis revealed a 40-kD glycoprotein. By N-terminal protein sequencing and searching of a cDNA database, Novick et al. (1999) isolated a T-cell IL18BP cDNA. Sequence analysis revealed that IL18BP encodes a 192-amino acid soluble protein with a 28-amino acid signal sequence. By analysis of a genomic clone, the authors identified 3 splice variants, which they termed IL18BPa (IL18BP; the predominant form), IL18BPb (a rare, shorter variant), and IL18BPc (a longer variant). Northern blot analysis revealed expression of a major 1.8-kb IL18BP transcript with highest intensity in spleen and lower intensity in thymus, peripheral blood leukocytes, prostate, small intestine, and colon.
Belkaya et al. (2019) found that IL18 and IL18BP are expressed in the liver. IL18 is mostly produced by macrophages, and induces IFN-gamma production, which in turn triggers intrahepatic IL18BP secretion, mostly from hepatocytes and macrophages. IFN-mediated IL18BP production can buffer intrahepatic IL18 activity through negative feedback.
Novick et al. (1999) determined that the IL18BP locus contains an additional gene, NUMA1 (164009), positioned at the minus strand. Thus, the IL18BP gene maps to chromosome 11q13, where the NUMA1 gene has been mapped.
Chemical crosslinking experiments by Aizawa et al. (1999) showed that recombinant IL18BP can bind to IL18. They demonstrated that recombinant IL18BP can prevent the binding of IL18 to its receptor and inhibit IL18-induced IFN-gamma (IFNG; 147570) production by the human myelomonocytic cell line KG-1.
Novick et al. (1999) showed that IL18BP eliminates IL18 induction of IFNG and IL8 (146930), and the activation of NFKB (164011) in vitro. Recombinant IL18BP inhibited lipopolysaccharide-induced IFNG production in mice.
By immunohistochemical analysis, Corbaz et al. (2002) showed that IL18BP expression in intestinal tissue is increased in endothelial cells as well as cells of the submucosa and overlying lymphoid aggregates in Crohn disease (IBD1; 266600) 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.
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.
In an 11-year-old girl, born of consanguineous Algerian parents, with fulminant viral hepatitis (FVH; 618549) associated with acute infection with hepatitis A, Belkaya et al. (2019) identified a homozygous 40-bp deletion in the IL18BP gene (604113.0001), resulting in splicing abnormalities and complete IL18BP deficiency. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the abnormal transcripts resulting from the mutation were unable to block any IL18 activity compared to wildtype or missense variants. Patient liver tissue showed high IL18 levels, barely detectable IL18BP, and high levels of inflammatory cells. Additional in vitro cellular studies showed that in the wildtype state, IL18-activated NK cells killed both infected and uninfected hepatocytes, and that this cytotoxicity was reversed by the addition of IL18BP. The findings indicated that absence of IL18BP in the patient with fulminant viral hepatitis due to hepatitis A led to uncontrolled IL18-mediated cytotoxic activity and an activated host response against hepatocytes.
Nowarski et al. (2015) found that deletion of Il18 or its receptor, Il18r1 (604494), 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.
In an 11-year-old girl, born of consanguineous Algerian parents, with fulminant viral hepatitis (FVH; 618549) associated with acute infection with hepatitis A, Belkaya et al. (2019) identified a homozygous 40-bp deletion (c.508-19_528del, NM_173042.2) in the IL18BP gene, which deletes 19 bp from the fourth and last intron and 21 contiguous nucleotides from the fifth and last exon. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes Project, or gnomAD databases, or in several in-house databases. Analysis of patient cells and cells from heterozygous family members showed that the mutation causes aberrant splicing with 3 abnormal transcripts, 2 of which were rapidly degraded, thus likely causing complete IL18BP deficiency in the patient. In vitro functional expression studies showed that the abnormal transcripts were unable to block any IL18 activity compared to wildtype or missense variants.
Aizawa, Y., Akita, K., Taniai, M., Torigoe, K., Mori, T., Nishida, Y., Ushio, S., Nukada, Y., Tanimoto, T., Ikegami, H., Ikeda, M., Kurimoto, M. Cloning and expression of interleukin-18 binding protein. FEBS Lett. 445: 338-342, 1999. [PubMed: 10094485] [Full Text: https://doi.org/10.1016/s0014-5793(99)00148-9]
Belkaya, S., Michailidis, E., Korol, C. B., Kabbani, M., Cobat, A., Bastard, P., Lee, Y. S., Hernandez, N., Drutman, S., de Jong, Y. P., Vivier, E., Bruneau, J., and 11 others. Inherited IL-18BP deficiency in human fulminant viral hepatitis. J. Exp. Med. 216: 1777-1790, 2019. [PubMed: 31213488] [Full Text: https://doi.org/10.1084/jem.20190669]
Corbaz, A., ten Hove, T., Herren, S., Graber, P., Schwartsburd, B., Belzer, I., Harrison, J., Plitz, T., Kosco-Vilbois, M. H., Kim, S.-H., Dinarello, C. A., Novick, D., van Deventer, S., Chvatchko, Y. IL-18-binding protein expression by endothelial cells and macrophages is up-regulated during active Crohn's disease. J. Immun. 168: 3608-3616, 2002. [PubMed: 11907126] [Full Text: https://doi.org/10.4049/jimmunol.168.7.3608]
Novick, D., Kim, S. H., Fantuzzi, G., Reznikov, L. L., Dinarello, C. A., Rubinstein, M. Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. Immunity 10: 127-136, 1999. [PubMed: 10023777] [Full Text: https://doi.org/10.1016/s1074-7613(00)80013-8]
Nowarski, R., Jackson, R., Gagliani, N., de Zoete, M. R., Palm, N. W., Bailis, W., Low, J. S., Harman, C. C. D., Graham, M., Elinav, E., Flavell, R. A. Epithelial IL-18 equilibrium controls barrier function in colitis. Cell 163: 1444-1456, 2015. [PubMed: 26638073] [Full Text: https://doi.org/10.1016/j.cell.2015.10.072]
ten Hove, T., Corbaz, A., Amitai, H., Aloni, S., Belzer, I., Graber, P., Drillenburg, P., van Deventer, S. J. H., Chvatchko, Y., te Velde, A. A. Blockade of endogenous IL-18 ameliorates TNBS-induced colitis by decreasing local TNF-alpha production in mice. Gastroenterology 121: 1372-1379, 2001. [PubMed: 11729116] [Full Text: https://doi.org/10.1053/gast.2001.29579]
Zhou, T., Damsky, W., Weizman, O.-E., McGeary, M. K., Hartmann, K. P., Rosen, C. E., Fischer, S., Jackson, R., Flavell, R. A., Wang, J., Sanmamed, M. F., Bosenberg, M. W., Ring, A. M. IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy. Nature 583: 609-614, 2020. [PubMed: 32581358] [Full Text: https://doi.org/10.1038/s41586-020-2422-6]