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Gene Review

IL18BP  -  interleukin 18 binding protein

Homo sapiens

Synonyms: IL-18BP, IL18BPa, Interleukin-18-binding protein, Tadekinig-alfa
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Disease relevance of IL18BP


High impact information on IL18BP

  • By neutralizing IL-18 activity with IL-18 binding protein (IL-18BP), we observed that islets produce bioactive IL-18 [6].
  • In vivo, transgenic mice overproducing IL-18BP (IL-18BP-Tg) exhibited delayed hyperglycemia induced by beta cell toxic streptozotocin [6].
  • The high-affinity, constitutively expressed, and circulating IL-18 binding protein (IL-18BP), which competes with cell surface receptors for IL-18 and neutralizes IL-18 activity, may act as a natural antiinflammatory as well as immunosuppressive molecule [7].
  • IL-18BP treatment also preserved intracellular tissue creatine kinase levels (by 420%) [8].
  • IL-18 alone had no direct effect on IL-18BP production by PBMCs or RA synovial cells, with or without stimulation [9].

Biological context of IL18BP

  • OBJECTIVE: To measure serum interleukin 18 (IL18) and IL18 binding protein (IL18BP) levels in patients with inflammatory arthropathies, and to identify associations with disease status and the response to treatment [10].
  • Molecular modelling identified a large mixed electrostatic and hydrophobic binding site in the immunoglobulin domain of IL18BP, which could account for its high affinity binding to the ligand [11].
  • However, none of these were frequent enough to permit association studies in T1DM and we conclude that IL18BP does not contribute to the overall genetic susceptibility to type 1 diabetes [12].
  • We evaluated the human IL18BP gene on chromosome 11q13 as a candidate susceptibility gene for T1DM and scanned the entire IL18BP (promoter, exons 1-6, and 3'UTR) for polymorphisms using single-strand conformational polymorphism analysis and direct sequencing [12].
  • We concluded that a severe IL-18/IL-18BP imbalance results in Th-1 lymphocyte and macrophage activation, which escapes control by NK-cell cytotoxicity and may allow for secondary HPS in patients with underlying diseases [4].

Anatomical context of IL18BP


Associations of IL18BP with chemical compounds

  • Also, IL18BP treatment preserved intracellular tissue creatine kinase levels (by 420%) [17].
  • The activity of IL-18 can be regulated by the IL-18-binding protein (IL-18BP), a glycoprotein of 40,000 daltons, which is constitutively expressed and appears to be the natural inhibitor of IL-18 activity [1].
  • Using surface plasmon resonance, we identified seven amino acids of hIL-18BP which, when changed individually to alanine, caused an 8-750-fold decrease in binding affinity, largely because of increased off-rates [18].
  • Furthermore, when the nonconserved valine of MC54L was mutated to phenylalanine, making it more like hIL-18BP, its affinity for hIL-18 increased more than 10-fold [19].
  • Plasma IL-18BP was inversely correlated with creatinine clearance (correlation coefficient: -0.7479) [20].

Regulatory relationships of IL18BP

  • IL-18BP reduced S. epidermidis-induced IFN-gamma (77% maximal suppression) [21].
  • S. epidermidis-induced TNF-alpha was inhibited by IL-18BP and IL-1Ra, but not anti-IL-12 Ab, whereas IL-8 production was unaffected by any of the specific cytokine blocking agents [21].
  • An equimolar concentration IL-18BP inhibited 90% of IL-18 activity, whereas a 4-fold molar excess of sIL-18Ralpha had no effect [22].

Other interactions of IL18BP

  • CONCLUSION: The production of IL-18BP in response to IL-12 and IL-18 was regulated differently in blood and synovial cells [9].
  • Unstimulated whole blood samples from RA patients showed lower levels of IL-18BP mRNA expression than those from healthy controls [9].
  • IL-18BP and interferon-gamma (IFN gamma) levels in supernatants were measured by enzyme-linked immunosorbent assay [9].
  • IFN-alpha administration increased IL-18BP plasma levels 3.24 fold 24 h after institution of therapy, resulting in a 67.4% reduction of free IL-18 [2].
  • IL-18 signals through a two-chain receptor (IL-18R and accessory protein-like subunit, AcPL), and an inhibitory molecule, IL-18 binding protein (IL-18BP), has recently been characterized [23].

Analytical, diagnostic and therapeutic context of IL18BP


  1. Interleukin 18 and interleukin 18 binding protein: possible role in immunosuppression of chronic renal failure. Dinarello, C.A., Novick, D., Rubinstein, M., Lonnemann, G. Blood Purif. (2003) [Pubmed]
  2. Interferon-alpha induces interleukin-18 binding protein in chronic hepatitis C patients. Kaser, A., Novick, D., Rubinstein, M., Siegmund, B., Enrich, B., Koch, R.O., Vogel, W., Kim, S.H., Dinarello, C.A., Tilg, H. Clin. Exp. Immunol. (2002) [Pubmed]
  3. IL-18 binding protein increases spontaneous and IL-1-induced prostaglandin production via inhibition of IFN-gamma. Reznikov, L.L., Kim, S.H., Westcott, J.Y., Frishman, J., Fantuzzi, G., Novick, D., Rubinstein, M., Dinarello, C.A. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  4. Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome. Mazodier, K., Marin, V., Novick, D., Farnarier, C., Robitail, S., Schleinitz, N., Veit, V., Paul, P., Rubinstein, M., Dinarello, C.A., Harlé, J.R., Kaplanski, G. Blood (2005) [Pubmed]
  5. Interleukin-18 and glycosaminoglycan binding by a protein encoded by Variola virus. Esteban, D.J., Nuara, A.A., Buller, R.M. J. Gen. Virol. (2004) [Pubmed]
  6. Responses of IL-18- and IL-18 receptor-deficient pancreatic islets with convergence of positive and negative signals for the IL-18 receptor. Lewis, E.C., Dinarello, C.A. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  7. Site-specific mutations in the mature form of human IL-18 with enhanced biological activity and decreased neutralization by IL-18 binding protein. Kim, S.H., Azam, T., Yoon, D.Y., Reznikov, L.L., Novick, D., Rubinstein, M., Dinarello, C.A. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  8. Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1beta. Pomerantz, B.J., Reznikov, L.L., Harken, A.H., Dinarello, C.A. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  9. Regulation of interleukin-18 binding protein production by blood and synovial cells from patients with rheumatoid arthritis. Kawashima, M., Novick, D., Rubinstein, M., Miossec, P. Arthritis Rheum. (2004) [Pubmed]
  10. 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]
  11. Targeting interleukin 18 with interleukin 18 binding protein. Dinarello, C.A. Ann. Rheum. Dis. (2000) [Pubmed]
  12. Mutation scan of a type 1 diabetes candidate gene: the human interleukin-18 binding protein gene. Nolsøe, R.L., Pociot, F., Novick, D., Rubinstein, M., Kim, S.H., Dinarello, C.A., Mandrup-Poulsen, T. Ann. N. Y. Acad. Sci. (2003) [Pubmed]
  13. IL-18-binding protein expression by endothelial cells and macrophages is up-regulated during active Crohn's disease. 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. J. Immunol. (2002) [Pubmed]
  14. Evidence for the expression of interleukin (IL)-18, IL-18 receptor and IL-18 binding protein in the human endometrium. Yoshino, O., Osuga, Y., Koga, K., Tsutsumi, O., Yano, T., Fujii, T., Kugu, K., Momoeda, M., Fujiwara, T., Tomita, K., Taketani, Y. Mol. Hum. Reprod. (2001) [Pubmed]
  15. Interferon-gamma mediates gene expression of IL-18 binding protein in nonleukocytic cells. Mühl, H., Kämpfer, H., Bosmann, M., Frank, S., Radeke, H., Pfeilschifter, J. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  16. A switch to high-flux helixone membranes reverses suppressed interferon-gamma production in patients on low-flux dialysis. Lonnemann, G., Novick, D., Rubinstein, M., Passlick-Deetjen, J., Lang, D., Dinarello, C.A. Blood Purif. (2003) [Pubmed]
  17. Novel targets for interleukin 18 binding protein. Dinarello, C.A. Ann. Rheum. Dis. (2001) [Pubmed]
  18. Determination of the functional epitopes of human interleukin-18-binding protein by site-directed mutagenesis. Xiang, Y., Moss, B. J. Biol. Chem. (2001) [Pubmed]
  19. Correspondence of the functional epitopes of poxvirus and human interleukin-18-binding proteins. Xiang, Y., Moss, B. J. Virol. (2001) [Pubmed]
  20. Interleukin-18, interleukin-18 binding protein and impaired production of interferon-gamma in chronic renal failure. Lonnemann, G., Novick, D., Rubinstein, M., Dinarello, C.A. Clin. Nephrol. (2003) [Pubmed]
  21. Regulation of Staphylococcus epidermidis-induced IFN-gamma in whole human blood: the role of endogenous IL-18, IL-12, IL-1, and TNF. Stuyt, R.J., Kim, S.H., Reznikov, L.L., Fantuzzi, G., Novick, D., Rubinstein, M., Kullberg, B.J., van der Meer, J.W., Dinarello, C.A., Netea, M.G. Cytokine (2003) [Pubmed]
  22. The combination of soluble IL-18Ralpha and IL-18Rbeta chains inhibits IL-18-induced IFN-gamma. Reznikov, L.L., Kim, S.H., Zhou, L., Bufler, P., Goncharov, I., Tsang, M., Dinarello, C.A. J. Interferon Cytokine Res. (2002) [Pubmed]
  23. Human keratinocytes constitutively produce but do not process interleukin-18. Mee, J.B., Alam, Y., Groves, R.W. Br. J. Dermatol. (2000) [Pubmed]
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