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Gene Review

IL18  -  interleukin 18

Homo sapiens

Synonyms: IFN-gamma-inducing factor, IGIF, IL-1 gamma, IL-18, IL-1g, ...
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Disease relevance of IL18


Psychiatry related information on IL18


High impact information on IL18


Chemical compound and disease context of IL18

  • Inhibition of tumor necrosis factor (TNF) activity by the addition of TNF-binding protein reduced IL-18-stimulated HIV-1 production by 48% [14].
  • Ex vivo stimulation of whole blood with heat-killed S. aureus markedly increased IL-1beta and IL-18 levels more than E. coli lipopolysaccharide stimulation [15].
  • In sarcoidosis and HP patients, thalidomide induced a dose-dependent, partial suppression of lipopolysacchride (LPS)-stimulated TNF-alpha, IL-12p40 and IL-18 release [16].
  • The purpose of this study was to determine tissue expression and serum levels of IL-18 in head and neck squamous cell carcinoma (HNSCC) and to evaluate ethanol and endotoxin-driven cytokine secretion [17].
  • Finally, unlike IL-12 p40 mRNA, the constitutive accumulation of IL-18 transcripts by unstimulated cells was amplified in the presence of the translational blocker cycloheximide, which also caused a superinduction of IL-18 expression after Staphylococcus aureus stimulation [18].

Biological context of IL18

  • Furthermore, lymphoproliferative signal pathways were active in MCLs compared with normal B cells, because genes encoding, e.g., IL10R alpha and IL18 were up-regulated, as were oncogenes like Bcl-2 and MERTK [19].
  • To evaluate whether common variation elsewhere in the gene was associated with disease susceptibility, we analyzed eight IL18 tag SNPs in a type 1 diabetic case-control collection (1,561 case and 1,721 control subjects) [20].
  • RESULTS: We have identified 5 novel SNPs in the IL18 gene (-920[t/c], -133[c/g], and -132[a/g] in promoter 2 [upstream of exon 2]; +179[c/a; Ser35Ser] in exon 4; and +486[c/t; Phe137Phe] in exon 6) [21].
  • BACKGROUND: Atopy has been linked to chromosome 11q22, a region that harbors the IL18 gene [21].
  • OBJECTIVE: We sought to investigate whether genetic abnormalities in the regulatory regions of the IL18 gene predispose, in part, to susceptibility to atopy [21].

Anatomical context of IL18


Associations of IL18 with chemical compounds

  • The IL18 precursor requires cleavage into an active, mature molecule by the intracellular cysteine protease, IL1beta converting enzyme (ICE, or caspase-1) [26].
  • RESULTS: The latex allergy phenotype was significantly associated with promoter polymorphisms in IL13 -1055 (P = 0.02), IL18 -607 (P = 0.02), and IL18 -656 (P = 0.02) compared with nonatopic controls [27].
  • After six months' treatment with methotrexate, IL18 levels were reduced, but the differences were not significant (p=0.052) [28].
  • In a simple 24-h human whole blood culture, IFN-gamma was produced by the combination of lipopolysaccharide (LPS) plus IL-18 [29].
  • Using actinomycin D, we also showed that IL-18 mRNA is unstable in FLSs [30].
  • In response to IL-18 stimulation, these cells produced large amounts of TNFalpha [31].

Physical interactions of IL18


Enzymatic interactions of IL18

  • In contrast to the activation of proIL-1beta by amebic lysates, the purified proteinase cleaved proIL-18 and mature IL-18 to biologically inactive fragments [36].
  • Molluscum contagiosum virus interleukin-18 (IL-18) binding protein is secreted as a full-length form that binds cell surface glycosaminoglycans through the C-terminal tail and a furin-cleaved form with only the IL-18 binding domain [37].

Regulatory relationships of IL18


Other interactions of IL18

  • In purified natural killer cells, IL-18 induced IL-8 that was also inhibited by TNF binding protein [38].
  • We conclude that IL-18 possesses proinflammatory properties by direct stimulation of gene expression and synthesis of TNFalpha from CD3+/CD4+ and natural killer cells with subsequent production of IL-1beta and IL-8 from the CD14+ population [38].
  • Stimulation of U1 cells with IL-18 resulted in increased production of IL-6, and exogenous IL-6 added to U1 cells increased HIV-1 production 4-fold over control [14].
  • Incubation with IL-12 and IL-18 in combination partially reversed the defective IFN-gamma production by posttransplantation patient PBMCs [43].
  • CONCLUSION: Our results show that expression of IL-18 is associated with that of IL-1beta and TNFalpha and with local inflammation in the synovial tissue of patients with RA [40].

Analytical, diagnostic and therapeutic context of IL18

  • Protein levels of IL18, MMPs, and TIMPs were measured by ELISA [25].
  • Gene expression of IL18, IL18Ralpha, IL18Rbeta, MMPs, and aggrecanases was detected by RT-PCR [25].
  • In cross sectional analyses, no correlations between IL18 levels and measures of disease activity or structural damage in RA were found [28].
  • In conclusion, short-term exposure of CD56+ cells to IL15/IL12 or IL15/IL18 at 8-day intervals may hold a promise for improved clinical results in cellular adoptive cancer immunotherapy and for the in vivo injections of the monokines [44].
  • RESULTS: Total RNA samples extracted from human gastric mucosa were reverse transcribed and analysed for TNFA, IL18 and ACTB by TaqMan real-time PCR [45].


  1. Single nucleotide polymorphisms of the IL18 gene are associated with atopic eczema. Novak, N., Kruse, S., Potreck, J., Maintz, L., Jenneck, C., Weidinger, S., Fimmers, R., Bieber, T. J. Allergy Clin. Immunol. (2005) [Pubmed]
  2. IL18 polymorphism is associated with an increased risk of Crohn's disease. Tamura, K., Fukuda, Y., Sashio, H., Takeda, N., Bamba, H., Kosaka, T., Fukui, S., Sawada, K., Tamura, K., Satomi, M., Yamada, T., Yamamura, T., Yamamoto, Y., Furuyama, J., Okamura, H., Shimoyama, T. J. Gastroenterol. (2002) [Pubmed]
  3. Human pancreatic carcinoma cells secrete bioactive interleukin-18 after treatment with 5-fluorouracil: implications for anti-tumor immune response. Carbone, A., Rodeck, U., Mauri, F.A., Sozzi, M., Gaspari, F., Smirne, C., Prati, A., Addeo, A., Novarino, A., Robecchi, A., Bertetto, O., Emanuelli, G., Bellone, G. Cancer Biol. Ther. (2005) [Pubmed]
  4. Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. Gerdes, N., Sukhova, G.K., Libby, P., Reynolds, R.S., Young, J.L., Schönbeck, U. J. Exp. Med. (2002) [Pubmed]
  5. Elevated levels of interleukin-18 predict the development of type 2 diabetes: results from the MONICA/KORA Augsburg Study, 1984-2002. Thorand, B., Kolb, H., Baumert, J., Koenig, W., Chambless, L., Meisinger, C., Illig, T., Martin, S., Herder, C. Diabetes (2005) [Pubmed]
  6. Soluble interleukin-1 receptor type II, IL-18 and caspase-1 in mild cognitive impairment and severe Alzheimer's disease. Lindberg, C., Chromek, M., Ahrengart, L., Brauner, A., Schultzberg, M., Garlind, A. Neurochem. Int. (2005) [Pubmed]
  7. IL-18 in patients with multiple sclerosis. Losy, J., Niezgoda, A. Acta neurologica Scandinavica. (2001) [Pubmed]
  8. Aerobic exercise, but not flexibility/resistance exercise, reduces serum IL-18, CRP, and IL-6 independent of beta-blockers, BMI, and psychosocial factors in older adults. Kohut, M.L., McCann, D.A., Russell, D.W., Konopka, D.N., Cunnick, J.E., Franke, W.D., Castillo, M.C., Reighard, A.E., Vanderah, E. Brain Behav. Immun. (2006) [Pubmed]
  9. Serum and cerebrospinal fluid levels of interleukin-18 in human immunodeficiency virus type 1-associated central nervous system disease. von Giesen, H.J., Jander, S., Köller, H., Arendt, G. J. Neurovirol. (2004) [Pubmed]
  10. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Döffinger, R., Smahi, A., Bessia, C., Geissmann, F., Feinberg, J., Durandy, A., Bodemer, C., Kenwrick, S., Dupuis-Girod, S., Blanche, S., Wood, P., Rabia, S.H., Headon, D.J., Overbeek, P.A., Le Deist, F., Holland, S.M., Belani, K., Kumararatne, D.S., Fischer, A., Shapiro, R., Conley, M.E., Reimund, E., Kalhoff, H., Abinun, M., Munnich, A., Israël, A., Courtois, G., Casanova, J.L. Nat. Genet. (2001) [Pubmed]
  11. Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Ghayur, T., Banerjee, S., Hugunin, M., Butler, D., Herzog, L., Carter, A., Quintal, L., Sekut, L., Talanian, R., Paskind, M., Wong, W., Kamen, R., Tracey, D., Allen, H. Nature (1997) [Pubmed]
  12. Cloning of a new cytokine that induces IFN-gamma production by T cells. Okamura, H., Tsutsi, H., Komatsu, T., Yutsudo, M., Hakura, A., Tanimoto, T., Torigoe, K., Okura, T., Nukada, Y., Hattori, K. Nature (1995) [Pubmed]
  13. Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme. Gu, Y., Kuida, K., Tsutsui, H., Ku, G., Hsiao, K., Fleming, M.A., Hayashi, N., Higashino, K., Okamura, H., Nakanishi, K., Kurimoto, M., Tanimoto, T., Flavell, R.A., Sato, V., Harding, M.W., Livingston, D.J., Su, M.S. Science (1997) [Pubmed]
  14. Interleukin 18 stimulates HIV type 1 in monocytic cells. Shapiro, L., Puren, A.J., Barton, H.A., Novick, D., Peskind, R.L., Shenkar, R., Gu, Y., Su, M.S., Dinarello, C.A. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  15. Molecular characterization of the acute inflammatory response to infections with gram-negative versus gram-positive bacteria. Feezor, R.J., Oberholzer, C., Baker, H.V., Novick, D., Rubinstein, M., Moldawer, L.L., Pribble, J., Souza, S., Dinarello, C.A., Ertel, W., Oberholzer, A. Infect. Immun. (2003) [Pubmed]
  16. Thalidomide reduces IL-18, IL-8 and TNF-{alpha} release from alveolar macrophages in interstitial lung disease. Ye, Q., Chen, B., Tong, Z., Nakamura, S., Sarria, R., Costabel, U., Guzman, J. Eur. Respir. J. (2006) [Pubmed]
  17. Expression of IL-18 in patients with head and neck squamous cell carcinoma. Riedel, F., Adam, S., Feick, P., Haas, S., Götte, K., Hörmann, K. Int. J. Mol. Med. (2004) [Pubmed]
  18. Regulation of human IL-18 mRNA expression. Marshall, J.D., Aste-Amézaga, M., Chehimi, S.S., Murphy, M., Olsen, H., Trinchieri, G. Clin. Immunol. (1999) [Pubmed]
  19. Mantle cell lymphomas express a distinct genetic signature affecting lymphocyte trafficking and growth regulation as compared with subpopulations of normal human B cells. Ek, S., Högerkorp, C.M., Dictor, M., Ehinger, M., Borrebaeck, C.A. Cancer Res. (2002) [Pubmed]
  20. Analysis of polymorphisms of the interleukin-18 gene in type 1 diabetes and Hardy-Weinberg equilibrium testing. Szeszko, J.S., Howson, J.M., Cooper, J.D., Walker, N.M., Twells, R.C., Stevens, H.E., Nutland, S.L., Todd, J.A. Diabetes (2006) [Pubmed]
  21. Polymorphisms in the IL 18 gene are associated with specific sensitization to common allergens and allergic rhinitis. Kruse, S., Kuehr, J., Moseler, M., Kopp, M.V., Kurz, T., Deichmann, K.A., Foster, P.S., Mattes, J. J. Allergy Clin. Immunol. (2003) [Pubmed]
  22. Dominant role for TL1A/DR3 pathway in IL-12 plus IL-18-induced IFN-gamma production by peripheral blood and mucosal CCR9+ T lymphocytes. Papadakis, K.A., Zhu, D., Prehn, J.L., Landers, C., Avanesyan, A., Lafkas, G., Targan, S.R. J. Immunol. (2005) [Pubmed]
  23. cis-Element clustering correlates with dose-dependent pro- and antisignaling effects of IL18. Leyfer, D., Bond, A., Tworog, E., Perron, D., Maska, S., Brito, A., Kamens, J., Weng, Z., Voss, J. Genes Immun. (2004) [Pubmed]
  24. Raised plasma concentration and ex vivo production of inflammatory chemokines in patients with systemic lupus erythematosus. Lit, L.C., Wong, C.K., Tam, L.S., Li, E.K., Lam, C.W. Ann. Rheum. Dis. (2006) [Pubmed]
  25. Implication of interleukin 18 in production of matrix metalloproteinases in articular chondrocytes in arthritis: direct effect on chondrocytes may not be pivotal. Dai, S.M., Shan, Z.Z., Nishioka, K., Yudoh, K. Ann. Rheum. Dis. (2005) [Pubmed]
  26. Novel targets for interleukin 18 binding protein. Dinarello, C.A. Ann. Rheum. Dis. (2001) [Pubmed]
  27. Genetic predisposition to latex allergy: role of interleukin 13 and interleukin 18. Brown, R.H., Hamilton, R.G., Mintz, M., Jedlicka, A.E., Scott, A.L., Kleeberger, S.R. Anesthesiology (2005) [Pubmed]
  28. Serum interleukin 18 and interleukin 18 binding protein in rheumatoid arthritis. Bresnihan, B., Roux-Lombard, P., Murphy, E., Kane, D., FitzGerald, O., Dayer, J.M. Ann. Rheum. Dis. (2002) [Pubmed]
  29. Interleukin-18 enhances lipopolysaccharide-induced interferon-gamma production in human whole blood cultures. Puren, A.J., Razeghi, P., Fantuzzi, G., Dinarello, C.A. J. Infect. Dis. (1998) [Pubmed]
  30. Impaired release of IL-18 from fibroblast-like synoviocytes activated with protein I/II, a pathogen-associated molecular pattern from oral streptococci, results from defective translation of IL-18 mRNA in pro-IL-18. Zeisel, M.B., Neff, L.A., Randle, J., Klein, J.P., Sibilia, J., Wachsmann, D. Cell. Microbiol. (2004) [Pubmed]
  31. Evidence for a pathogenetic role of interleukin-18 in cutaneous lupus erythematosus. Wang, D., Drenker, M., Eiz-Vesper, B., Werfel, T., Wittmann, M. Arthritis Rheum. (2008) [Pubmed]
  32. IL-12 induces monocyte IL-18 binding protein expression via IFN-gamma. Veenstra, K.G., Jonak, Z.L., Trulli, S., Gollob, J.A. J. Immunol. (2002) [Pubmed]
  33. IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp. Pan, G., Risser, P., Mao, W., Baldwin, D.T., Zhong, A.W., Filvaroff, E., Yansura, D., Lewis, L., Eigenbrot, C., Henzel, W.J., Vandlen, R. Cytokine (2001) [Pubmed]
  34. Rational design of an EGF-IL18 fusion protein: implication for developing tumor therapeutics. Lu, J.X., Peng, Y., Meng, Z.F., Jin, L.Q., Lu, Y.S., Guan, M.X. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  35. Interleukin-18 secretion and Th1-like cytokine responses in human peripheral blood mononuclear cells under the influence of the toll-like receptor-5 ligand flagellin. Bachmann, M., Horn, K., Poleganov, M.A., Paulukat, J., Nold, M., Pfeilschifter, J., Mühl, H. Cell. Microbiol. (2006) [Pubmed]
  36. A surface amebic cysteine proteinase inactivates interleukin-18. Que, X., Kim, S.H., Sajid, M., Eckmann, L., Dinarello, C.A., McKerrow, J.H., Reed, S.L. Infect. Immun. (2003) [Pubmed]
  37. Molluscum contagiosum virus interleukin-18 (IL-18) binding protein is secreted as a full-length form that binds cell surface glycosaminoglycans through the C-terminal tail and a furin-cleaved form with only the IL-18 binding domain. Xiang, Y., Moss, B. J. Virol. (2003) [Pubmed]
  38. Interleukin-18 (IFNgamma-inducing factor) induces IL-8 and IL-1beta via TNFalpha production from non-CD14+ human blood mononuclear cells. Puren, A.J., Fantuzzi, G., Gu, Y., Su, M.S., Dinarello, C.A. J. Clin. Invest. (1998) [Pubmed]
  39. Stabilization of IFN-gamma mRNA by MAPK p38 in IL-12- and IL-18-stimulated human NK cells. Mavropoulos, A., Sully, G., Cope, A.P., Clark, A.R. Blood (2005) [Pubmed]
  40. Association of interleukin-18 expression with enhanced levels of both interleukin-1beta and tumor necrosis factor alpha in knee synovial tissue of patients with rheumatoid arthritis. Joosten, L.A., Radstake, T.R., Lubberts, E., van den Bersselaar, L.A., van Riel, P.L., van Lent, P.L., Barrera, P., van den Berg, W.B. Arthritis Rheum. (2003) [Pubmed]
  41. Functional reconstitution and regulation of IL-18 activity by the IL-18R beta chain. Kim, S.H., Reznikov, L.L., Stuyt, R.J., Selzman, C.H., Fantuzzi, G., Hoshino, T., Young, H.A., Dinarello, C.A. J. Immunol. (2001) [Pubmed]
  42. Interleukin-18 induces angiogenic factors in rheumatoid arthritis synovial tissue fibroblasts via distinct signaling pathways. Amin, M.A., Mansfield, P.J., Pakozdi, A., Campbell, P.L., Ahmed, S., Martinez, R.J., Koch, A.E. Arthritis Rheum. (2007) [Pubmed]
  43. Impaired interferon-gamma production as a consequence of STAT4 deficiency after autologous hematopoietic stem cell transplantation for lymphoma. Robertson, M.J., Chang, H.C., Pelloso, D., Kaplan, M.H. Blood (2005) [Pubmed]
  44. Beneficial effect of short-term exposure of human NK cells to IL15/IL12 and IL15/IL18 on cell apoptosis and function. Sotiriadou, N.N., Perez, S.A., Gritzapis, A.D., Mahaira, L.G., Salagianni, M., Baxevanis, C.N., Papamichail, M. Cell. Immunol. (2005) [Pubmed]
  45. Evaluation of absolute quantitation by nonlinear regression in probe-based real-time PCR. Goll, R., Olsen, T., Cui, G., Florholmen, J. BMC Bioinformatics (2006) [Pubmed]
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