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Role of IL-18 in inflammatory diseases

  • Chapter
New Therapeutic Targets in Rheumatoid Arthritis

Part of the book series: Progress in Inflammation Research ((PIR))

Abstract

IL-18 is a member of the interleukin (IL)-1 family. IL-1β and IL-18 are closely related, and both require the intracellular cysteine protease caspase-1 for biological activity. Several autoimmune diseases are thought to be mediated, in part, by IL-18. Many are those with associated elevated interferon-γ (IFN-γ) levels, such as systemic lupus erythematosus, macrophage activation syndrome, rheumatoid arthritis, Crohn’s disease, psoriasis and graft versus host disease. In addition, ischemia, including acute renal failure in humans, appears to involve IL-18. Animal studies also support the concept that IL-18 is a key player in models of lupus erythematosus, atherosclerosis, graft versus host disease and hepatitis. Unexpectedly, IL-18 plays a role in appetite control and the development of obesity. The IL-18-binding protein, a naturally occurring, specific inhibitor of IL-18, neutralizes IL-18 activities and has been shown to be safe in patients. Other options for reducing IL-18 activities are inhibitors of capsase-1, human monoclonal antibodies to IL-18, soluble IL-18 receptors and anti-IL-18 receptor monoclonal antibodies.

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References

  1. Okamura H, Tsutsui H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, Torigoe K, Okura T, Nukada Y, Hattori K et al (1995) Cloning of a new cytokine that induces interferon-γ. Nature 378: 88–91

    PubMed  CAS  Google Scholar 

  2. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X et al (2005) IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23: 479–490

    PubMed  CAS  Google Scholar 

  3. Ghayur T, Banerjee S, Hugunin M, Butler D, Herzog L, Carter A, Quintal L, Sekut L, Talanian R, Paskind M et al (1997) Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature 386: 619–623

    PubMed  CAS  Google Scholar 

  4. Gu Y, Kuida K, Tsutsui H, Ku G, Hsiao K, Fleming MA, Hayashi N, Higashino K, Okamura H, Nakanishi K et al (1997) Activation of interferon-γ inducing factor mediated by interleukin-1β converting enzyme. Science 275: 206–209

    PubMed  CAS  Google Scholar 

  5. Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, Roose-Girma M, Erickson S, Dixit VM (2004) Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430: 213–218

    PubMed  CAS  Google Scholar 

  6. Fantuzzi G, Puren AJ, Harding MW, Livingston DJ, Dinarello CA (1998) IL-18 regulation of IFN-γ production and cell proliferation as revealed in interleukin-1β converting enzyme-deficient mice. Blood 91: 2118–2125

    PubMed  CAS  Google Scholar 

  7. Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H (2001) Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu. Cytokine Growth Factor Rev 12: 53–72

    PubMed  CAS  Google Scholar 

  8. Siegmund B, Lehr HA, Fantuzzi G, Dinarello CA (2001) IL-1beta-converting enzyme (caspase-1) in intestinal inflammation. Proc Natl Acad Sci USA 98: 13249–13254

    PubMed  CAS  Google Scholar 

  9. Siegmund B, Fantuzzi G, Rieder F, Gamboni-Robertson F, Lehr HA, Hartmann G, Dinarello CA, Endres S, Eigler A (2001) Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-γ and TNF-α production. Am J Physiol Regul Integr Comp Physiol 281: R1264–1273

    PubMed  CAS  Google Scholar 

  10. Gatti S, Beck J, Fantuzzi G, Bartfai T, Dinarello CA (2002) Effect of interleukin-18 on mouse core body temperature. Am J Physiol Regul Integr Comp Physiol 282: R702–709

    PubMed  CAS  Google Scholar 

  11. Li S, Goorha S, Ballou LR, Blatteis CM (2003) Intracerebroventricular interleukin-6, macrophage inflammatory protein-1 beta and IL-18: Pyrogenic and PGE(2)-mediated? Brain Res 992: 76–84

    PubMed  CAS  Google Scholar 

  12. Reznikov LL, Kim SH, Westcott JY, Frishman J, Fantuzzi G, Novick D, Rubinstein M, Dinarello CA (2000) IL-18 binding protein increases spontaneous and IL-1-induced prostaglandin production via inhibition of IFN-gamma. Proc Natl Acad Sci USA 97: 2174–2179

    PubMed  CAS  Google Scholar 

  13. Lee JK, Kim SH, Lewis EC, Azam T, Reznikov LL, Dinarello CA (2004) Differences in signaling pathways by IL-1beta and IL-18. Proc Natl Acad Sci USA 101: 8815–8820

    PubMed  CAS  Google Scholar 

  14. Kim SH, Han SY, Azam T, Yoon DY, Dinarello CA (2005) Interleukin-32: A cytokine and inducer of TNFalpha. Immunity 22: 131–142

    PubMed  CAS  Google Scholar 

  15. Joosten LA, van De Loo FA, Lubberts E, Helsen MM, Netea MG, van Der Meer JW, Dinarello CA, van Den Berg WB (2000) An IFN-gamma-independent proinflammatory role of IL-18 in murine streptococcal cell wall arthritis. J Immunol 165: 6553–6558

    PubMed  CAS  Google Scholar 

  16. Carrascal MT, Mendoza L, Valcarcel M, Salado C, Egilegor E, Telleria N, Vidal-Vanaclocha F, Dinarello CA (2003) Interleukin-18 binding protein reduces b16 melanoma hepatic metastasis by neutralizing adhesiveness and growth factors of sinusoidal endothelium. Cancer Res 63: 491–497

    PubMed  CAS  Google Scholar 

  17. Randle JC, Harding MW, Ku G, Schonharting M, Kurrle R (2001) ICE/caspase-1 inhibitors as novel anti-inflammatory drugs. Expert Opin Investig Drugs 10: 1207–1209

    PubMed  CAS  Google Scholar 

  18. Novick D, Kim S-H, Fantuzzi G, Reznikov L, Dinarello CA, Rubinstein M (1999) Interleukin-18 binding protein: A novel modulator of the Th1 cytokine response. Immunity 10: 127–136

    PubMed  CAS  Google Scholar 

  19. Novick D, Schwartsburd B, Pinkus R, Suissa D, Belzer I, Sthoeger Z, Keane WF, Chvatchko Y, Kim SH, Fantuzzi G et al (2001) A novel IL-18BP ELISA shows elevated serum il-18BP in sepsis and extensive decrease of free IL-18. Cytokine 14: 334–342

    PubMed  CAS  Google Scholar 

  20. Kim S-H, Eisenstein M, Reznikov L, Fantuzzi G, Novick D, Rubinstein M, Dinarello CA (2000) Structural requirements of six naturally occurring isoforms of the interleukin-18 binding protein to inhibit interleukin-18. Proc Natl Acad Sci USA 97: 1190–1195

    PubMed  CAS  Google Scholar 

  21. Tak PP, Bacchi M, Bertolino M (2006) Pharmacokinetics of IL-18 binding protein in healthy volunteers and subjects with rheumatoid arthritis or plaque psoriasis. Eur J Drug Metab Pharmacokinetics 31: 109–116

    CAS  Google Scholar 

  22. Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J (2004) NALP3 forms an IL-1β processing inflammasome with increased activity in Muckle-Wells auto-inflammatory disorder. Immunity 20: 319–325

    PubMed  CAS  Google Scholar 

  23. Aganna E, Martinon F, Hawkins PN, Ross JB, Swan DC, Booth DR, Lachmann HJ, Bybee A, Gaudet R, Woo P et al (2002) Association of mutations in the NALP3/CIAS1/ PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum 46: 2445–2452

    PubMed  CAS  Google Scholar 

  24. Hawkins PN, Lachmann HJ, Aganna E, McDermott MF (2004) Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum 50: 607–612

    PubMed  CAS  Google Scholar 

  25. Coeshott C, Ohnemus C, Pilyavskaya A, Ross S, Wieczorek M, Kroona H, Leimer AH, Cheronis J (1999) Converting enzyme-independent release of TNFα and IL-1β from a stimulated human monocytic cell line in the presence of activated neutrophils or purified proteinase-3. Proc Natl Acad Sci USA 96: 6261–6266

    PubMed  CAS  Google Scholar 

  26. Sugawara S, Uehara A, Nochi T, Yamaguchi T, Ueda H, Sugiyama A, Hanzawa K, Kumagai K, Okamura H, Takada H (2001) Neutrophil proteinase 3-mediated induction of bioactive IL-18 secretion by human oral epithelial cells. J Immunol 167: 6568–6575

    PubMed  CAS  Google Scholar 

  27. Faggioni R, Cattley RC, Guo J, Flores S, Brown H, Qi M, Yin S, Hill D, Scully S, Chen C et al (2001) IL-18-binding protein protects against lipopolysaccharide-induced lethality and prevents the development of Fas/Fas ligand-mediated models of liver disease in mice. J Immunol 167: 5913–5920

    PubMed  CAS  Google Scholar 

  28. Pomerantz BJ, Reznikov LL, Harken AH, Dinarello CA (2001) Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1beta. Proc Natl Acad Sci USA 98: 2871–2876

    PubMed  CAS  Google Scholar 

  29. Melnikov VY, Ecder T, Fantuzzi G, Siegmund B, Lucia MS, Dinarello CA, Schrier RW, Edelstein CL (2001) Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. J Clin Invest 107: 1145–1152

    PubMed  CAS  Google Scholar 

  30. Perregaux DG, McNiff P, Laliberte R, Conklyn M, Gabel CA (2000) ATP acts as an agonist to promote stimulus-induced secretion of IL-1 beta and IL-18 in human blood. J Immunol 165: 4615–4623

    PubMed  CAS  Google Scholar 

  31. Solle M, Labasi J, Perregaux DG, Stam E, Petrushova N, Koller BH, Griffiths RJ, Gabel CA (2001) Altered cytokine production in mice lacking P2X(7) receptors. J Biol Chem 276: 125–132

    PubMed  CAS  Google Scholar 

  32. Laliberte RE, Eggler J, Gabel CA (1999) ATP treatment of human monocytes promotes caspase-1 maturation and externalization. J Biol Chem 274: 36944–36951

    PubMed  CAS  Google Scholar 

  33. Baraldi PG, del Carmen Nunez M, Morelli A, Falzoni S, Di Virgilio F, Romagnoli R (2003) Synthesis and biological activity of N-arylpiperazine-modified analogues of KN-62, a potent antagonist of the purinergic P2X7 receptor. J Med Chem 46: 1318–1329

    PubMed  CAS  Google Scholar 

  34. Gardella S, Andrei C, Costigliolo S, Poggi A, Zocchi MR, Rubartelli A (1999) Interleukin-18 synthesis and secretion by dendritic cells are modulated by interaction with antigen-specific T cells. J Leukoc Biol 66: 237–241

    PubMed  CAS  Google Scholar 

  35. Gardella S, Andrei C, Poggi A, Zocchi MR, Rubartelli A (2000) Control of interleukin-18 secretion by dendritic cells: Role of calcium influxes.FEBS Lett 481: 245–248

    PubMed  CAS  Google Scholar 

  36. Kato Z, Jee J, Shikano H, Mishima M, Ohki I, Ohnishi H, Li A, Hashimoto K, Matsukuma E, Omoya K et al (2003) The structure and binding mode of interleukin-18. Nat Struct Biol 10: 966–971

    PubMed  CAS  Google Scholar 

  37. Azam T, Novick D, Bufler P, Yoon DY, Rubinstein M, Dinarello CA, Kim SH (2003) Identification of a critical Ig-like domain in IL-18 receptor alpha and characterization of a functional IL-18 receptor complex. J Immunol 171: 6574–6580

    PubMed  CAS  Google Scholar 

  38. Casadio R, Frigimelica E, Bossu P, Neumann D, Martin MU, Tagliabue A, Boraschi D (2001) Model of interaction of the IL-1 receptor accessory protein IL-1RAcP with the IL-1beta/IL-1R(I) complex. FEBS Lett 499: 65–68

    PubMed  CAS  Google Scholar 

  39. Reznikov LL, Kim SH, Zhou L, Bufler P, Goncharov I, Tsang M, Dinarello CA (2002) The combination of soluble IL-18Rα and IL-18Rβ chains inhibits IL-18-induced IFN-γ. J Interferon Cytokine Res 22: 593–601

    PubMed  CAS  Google Scholar 

  40. Kumar S, McDonnell PC, Lehr R, Tierney L, Tzimas MN, Griswold DE, Capper EA, Tal-Singer R, Wells GI, Doyle ML et al (2000) Identification and initial characterization of four novel members of the interleukin-1 family. J Biol Chem 275: 10308–10314

    PubMed  CAS  Google Scholar 

  41. Pan G, Risser P, Mao W, Baldwin DT, Zhong AW, Filvaroff E, Yansura D, Lewis L, Eigenbrot C, Henzel WJ et al (2001) IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp. Cytokine 13: 1–7

    PubMed  CAS  Google Scholar 

  42. Kumar S, Hanning CR, Brigham-Burke MR, Rieman DJ, Lehr R, Khandekar S, Kirkpatrick RB, Scott GF, Lee JC, Lynch FJ et al (2002) Interleukin-1F7B (IL-1H4/IL-1F7) is processed by caspase-1 and mature IL-1F7B binds to the IL-18 receptor but does not induce IFN-gamma production. Cytokine 18: 61–71

    PubMed  CAS  Google Scholar 

  43. Bufler P, Azam T, Gamboni-Robertson F, Reznikov LL, Kumar S, Dinarello CA, Kim SH (2002) A complex of the IL-1 homologue IL-1F7b and IL-18-binding protein reduces IL-18 activity. Proc Natl Acad Sci USA 99: 13723–13728

    PubMed  CAS  Google Scholar 

  44. Novick D, Engelmann H, Wallach D, Leitner O, Revel M, Rubinstein M (1990) Purification of soluble cytokine receptors from normal human urine by ligand-affinity and immunoaffinity chromatography. J Chromatogr 510: 331–337

    PubMed  CAS  Google Scholar 

  45. Engelmann H, Novick D, Wallach D (1990) Two tumor necrosis factor-binding proteins purified from human urine. Evidence for immunological cross-reactivity with cell surface tumor necrosis factor receptors. J Biol Chem 265: 1531–1536

    PubMed  CAS  Google Scholar 

  46. Kim SH, Azam T, Novick D, Yoon DY, Reznikov LL, Bufler P, Rubinstein M, Dinarello CA (2002) Identification of amino acid residues critical for biological activity in human interleukin-18. J Biol Chem 277: 10998–11003

    PubMed  CAS  Google Scholar 

  47. Dinarello CA (2005) The many worlds of reducing interleukin-1. Arthritis Rheum 52: 1960–1967

    PubMed  CAS  Google Scholar 

  48. Hurgin V, Novick D, Rubinstein M (2002) The promoter of IL-18 binding protein: Activation by an IFN-gamma-induced complex of IFN regulatory factor 1 and CCAAT/ enhancer binding protein beta. Proc Natl Acad Sci USA 99: 16957–16962

    PubMed  CAS  Google Scholar 

  49. Paulukat J, Bosmann M, Nold M, Garkisch S, Kampfer H, Frank S, Raedle J, Zeuzem S, Pfeilschifter J, Muhl H (2001) Expression and release of IL-18 binding protein in response to IFNγ. J Immunol 167: 7038–7043

    PubMed  CAS  Google Scholar 

  50. Fantuzzi G, Reed D, Qi M, Scully S, Dinarello CA, Senaldi G (2001) Role of interferon regulatory factor-1 in the regulation of IL-18 production and activity. Eur J Immunol 31: 369–375

    PubMed  CAS  Google Scholar 

  51. Siegmund B, Sennello JA, Lehr HA, Senaldi G, Dinarello CA, Fantuzzi G (2004) Interferon regulatory factor-1 as a protective gene in intestinal inflammation: Role of TCR gamma delta T cells and interleukin-18-binding protein. Eur J Immunol 34: 2356–2364

    PubMed  CAS  Google Scholar 

  52. Xiang Y, Moss B (2001) Correspondence of the functional epitopes of poxvirus and human interleukin-18-binding proteins. J Virol 75: 9947–9954

    PubMed  CAS  Google Scholar 

  53. Xiang Y, Moss B (2001) Determination of the functional epitopes of human interleukin-18-binding protein by site-directed mutagenesis. J Biol Chem 276: 17380–17386

    PubMed  CAS  Google Scholar 

  54. Maeno N, Takei S, Imanaka H, Yamamoto K, Kuriwaki K, Kawano Y, Oda H (2004) Increased interleukin-18 expression in bone marrow of a patient with systemic juvenile idiopathic arthritis and unrecognized macrophage-activation syndrome. Arthritis Rheum 50: 1935–1938

    PubMed  Google Scholar 

  55. Dinarello CA (2005) Differences between anti-tumor necrosis factor-alpha monoclonal antibodies and soluble TNF receptors in host defense impairment. J Rheumatol Suppl 74: 40–47

    PubMed  CAS  Google Scholar 

  56. Ottenhoff TH, Verreck FA, Lichtenauer-Kaligis EG, Hoeve MA, Sanal O, van Dissel JT (2002) Genetics, cytokines and human infectious disease: Lessons from weakly pathogenic mycobacteria and salmonellae. Nat Genet 32: 97–105

    PubMed  CAS  Google Scholar 

  57. Wei XQ, Leung BP, Arthur HM, McInnes IB, Liew FY (2001) Reduced incidence and severity of collagen-induced arthritis in mice lacking IL-18. J Immunol 166: 517–521

    PubMed  CAS  Google Scholar 

  58. Plater-Zyberk C, Joosten LA, Helsen MM, Sattonnet-Roche P, Siegfried C, Alouani S, van De Loo FA, Graber P, Aloni S, Cirillo R et al (2001) Therapeutic effect of neutralizing endogenous IL-18 activity in the collagen-induced model of arthritis. J Clin Invest 108: 1825–1832

    PubMed  CAS  Google Scholar 

  59. Bossu P, Neumann D, Del Giudice E, Ciaramella A, Gloaguen I, Fantuzzi G, Dinarello CA, Di Carlo E, Musiani P, Meroni PL et al (2003) IL-18 cDNA vaccination protects mice from spontaneous lupus-like autoimmune disease. Proc Natl Acad Sci USA 100: 14181–14186

    PubMed  CAS  Google Scholar 

  60. Kim SH, Reznikov LL, Stuyt RJ, Selzman CH, Fantuzzi G, Hoshino T, Young HA, Dinarello CA (2001) Functional reconstitution and regulation of IL-18 activity by the IL-18R beta chain. J Immunol 166: 148–154

    PubMed  CAS  Google Scholar 

  61. Neumann D, Martin MU (2001) Interleukin-12 upregulates the IL-18Rβ chain in BALB/c thymocytes. J Interferon Cytokine Res 21: 635–642

    PubMed  CAS  Google Scholar 

  62. Lugo-Villarino G, Maldonado-Lopez R, Possemato R, Penaranda C, Glimcher LH (2003) T-bet is required for optimal production of IFN-gamma and antigen-specific T cell activation by dendritic cells. Proc Natl Acad Sci USA 100: 7749–7754

    PubMed  CAS  Google Scholar 

  63. Cardoso SM, DeFor TE, Tilley LA, Bidwell JL, Weisdorf DJ, MacMillan ML (2004) Patient interleukin-18 GCG haplotype associates with improved survival and decreased transplant-related mortality after unrelated-donor bone marrow transplantation. Br J Haematol 126: 704–710

    PubMed  CAS  Google Scholar 

  64. Min CK, Maeda Y, Lowler K, Liu C, Clouthier S, Lofthus D, Weisiger E, Ferrara JL, Reddy P (2004) Paradoxical effects of interleukin-18 on the severity of acute graft-versus-host disease mediated by CD4+ and CD8+ T-cell subsets after experimental allogeneic bone marrow transplantation. Blood 104: 3393–3399

    PubMed  CAS  Google Scholar 

  65. Reddy P, Ferrara JL (2003) Role of interleukin-18 in acute graft-vs-host disease. J Lab Clin Med 141: 365–371

    PubMed  CAS  Google Scholar 

  66. Hoshino T, Yagita H, Ortaldo JR, Wiltrout RH, Young HA (2000) In vivo administration of IL-18 can induce IgE production through Th2 cytokine induction and up-regulation of CD40 ligand (CD154) expression on CD4+ T cells. Eur J Immunol 30: 1998–2006

    PubMed  CAS  Google Scholar 

  67. Kawase Y, Hoshino T, Yokota K, Kuzuhara A, Kirii Y, Nishiwaki E, Maeda Y, Takeda J, Okamoto M, Kato S et al (2003) Exacerbated and prolonged allergic and non-allergic inflammatory cutaneous reaction in mice with targeted interleukin-18 expression in the skin. J Invest Dermatol 121: 502–509

    PubMed  CAS  Google Scholar 

  68. Konishi H, Tsutsui H, Murakami T, Yumikura-Futatsugi S, Yamanaka K, Tanaka M, Iwakura Y, Suzuki N, Takeda K, Akira S et al (2002) IL-18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions. Proc Natl Acad Sci USA 99: 11340–11345

    PubMed  CAS  Google Scholar 

  69. Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H (2001) Interleukin-18 regulates both Th1 and Th2 responses. Ann Rev Immunol 19: 423–474

    CAS  Google Scholar 

  70. Kaser A, Kaser S, Kaneider NC, Enrich B, Wiedermann CJ, Tilg H (2004) Interleukin-18 attracts plasmacytoid dendritic cells (DC2s) and promotes Th1 induction by DC2s through IL-18 receptor expression. Blood 103: 648–655

    PubMed  CAS  Google Scholar 

  71. Frigerio S, Hollander GA, Zumsteg U (2002) Functional IL-18 Is produced by primary pancreatic mouse islets and NIT-1 beta cells and participates in the progression towards destructive insulitis. Horm Res 57: 94–104

    PubMed  CAS  Google Scholar 

  72. Hong TP, Andersen NA, Nielsen K, Karlsen AE, Fantuzzi G, Eizirik DL, Dinarello CA, Mandrup-Poulsen T (2000) Interleukin-18 mRNA, but not interleukin-18 receptor mRNA, is constitutively expressed in islet beta-cells and up-regulated by interferon-gamma. Eur Cytokine Netw 11: 193–205

    PubMed  CAS  Google Scholar 

  73. Oikawa Y, Shimada A, Kasuga A, Morimoto J, Osaki T, Tahara H, Miyazaki T, Tashiro F, Yamato E, Miyazaki J et al (2003) Systemic administration of IL-18 promotes diabetes development in young nonobese diabetic mice. J Immunol 171: 5865–5875

    PubMed  CAS  Google Scholar 

  74. Nicoletti F, Di Marco R, Papaccio G, Conget I, Gomis R, Bernardini R, Sims JE, Shoenfeld Y, Bendtzen K (2003) Essential pathogenic role of endogenous IL-18 in murine diabetes induced by multiple low doses of streptozotocin. Prevention of hyperglycemia and insulitis by a recombinant IL-18-binding protein: Fc construct. Eur J Immunol 33: 2278–2286

    PubMed  CAS  Google Scholar 

  75. Zaccone P, Phillips J, Conget I, Cooke A, Nicoletti F (2005) IL-18 binding protein fusion construct delays the development of diabetes in adoptive transfer and cyclophosph-amide-induced diabetes in NOD mouse. Clin Immunol 115: 74–79

    PubMed  CAS  Google Scholar 

  76. Lukic ML, Mensah-Brown E, Wei X, Shahin A, Liew FY (2003) Lack of the mediators of innate immunity attenuate the development of autoimmune diabetes in mice. J Autoimmun 21: 239–246

    PubMed  CAS  Google Scholar 

  77. Sarvetnick N (1997) IFN-gamma, IGIF, and IDDM. J Clin Invest 99: 371–372

    PubMed  CAS  Google Scholar 

  78. Raeburn CD, Dinarello CA, Zimmerman MA, Calkins CM, Pomerantz BJ, McIntyre RC Jr, Harken AH, Meng X (2002) Neutralization of IL-18 attenuates lipopolysaccharide-induced myocardial dysfunction. Am J Physiol 283: H650–657

    CAS  Google Scholar 

  79. Friteau L, Francesconi E, Lando D, Dugas B, Damais C (1988) Opposite effect of interferon-γ on PGE2 release from interleukin-1-stimulated human monocytes or fibroblasts. Biochem Biophys Res Commun 157: 1197–1204

    PubMed  CAS  Google Scholar 

  80. Mallat Z, Heymes C, Corbaz A, Logeart D, Alouani S, Cohen-Solal A, Seidler T, Hasenfuss G, Chvatchko Y, Shah AM et al (2004) Evidence for altered interleukin 18 (IL)-18 pathway in human heart failure. FASEB J 18: 1752–1754

    PubMed  CAS  Google Scholar 

  81. Whitman SC, Ravisankar P, Daugherty A (2002) Interleukin-18 enhances atherosclerosis in apolipoprotein E(-/-) mice through release of interferon-gamma. Circ Res 90: E34–38

    PubMed  CAS  Google Scholar 

  82. Gerdes N, Sukhova GK, Libby P, Reynolds RS, Young JL, Schonbeck U (2002) Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: Implications for atherogenesis. J Exp Med 195: 245–257

    PubMed  CAS  Google Scholar 

  83. Mallat Z, Corbaz A, Scoazec A, Graber P, Alouani S, Esposito B, Humbert Y, Chvatchko Y, Tedgui A (2001) Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res 89: E41–45

    PubMed  CAS  Google Scholar 

  84. Parikh CR, Jani A, Melnikov VY, Faubel S, Edelstein CL (2004) Urinary interleukin-18 is a marker of human acute tubular necrosis. Am J Kidney Dis 43: 405–414

    PubMed  CAS  Google Scholar 

  85. Parikh CR, Abraham E, Ancukiewicz M, Edelstein CL (2005) Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the ICU. J Am Soc Nephrol 16: 3046–3052

    PubMed  CAS  Google Scholar 

  86. Parikh CR, Mishra J, Thiessen-Philbrook H, Dursun B, Ma Q, Kelly C, Dent C, Devarajan P, Edelstein CL (2006) Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery. Kidney Int 70: 199–203

    PubMed  CAS  Google Scholar 

  87. Netea MG, Joosten LA, Lewis E, Jensen DR, Voshol PJ, Kullberg BJ, Tack CJ, van Krieken H, Kim SH, Stalenhoef AF et al (2006) Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance. Nat Med 12: 650–656

    PubMed  CAS  Google Scholar 

  88. Zorrilla EP, Sanchez-Alavez M, Sugama S, Brennan M, Fernandez R, Bartfai T, Conti B (2007) Interleukin-18 controls energy homeostasis by suppressing appetite and feed efficiency. Proc Natl Acad Sci USA 104: 11097–11102

    PubMed  CAS  Google Scholar 

  89. Stuyt RJ, Netea MG, Verschueren I, Dinarello CA, Kullberg BJ, van der Meer JW (2005) Interleukin-18 does not modulate the acute-phase response. J Endotoxin Res 11: 85–88

    PubMed  CAS  Google Scholar 

  90. Puren AJ, Fantuzzi G, Dinarello CA (1999) Gene expression, synthesis and secretion of IL-1β and IL-18 are differentially regulated in human blood mononuclear cells and mouse spleen cells. Proc Natl Acad Sci USA 96: 2256–2261

    PubMed  CAS  Google Scholar 

  91. Mazodier K, Marin V, Novick D, Farnarier C, Robitail S, Schleinitz N, Veit V, Paul P, Rubinstein M, Dinarello CA et al (2005) Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome. Blood 106: 3483–3489

    PubMed  CAS  Google Scholar 

  92. Sivakumar PV, Westrich GM, Kanaly S, Garka K, Born TL, Derry JM, Viney JL (2002) Interleukin 18 is a primary mediator of the inflammation associated with dextran sulphate sodium induced colitis: Blocking interleukin 18 attenuates intestinal damage. Gut 50: 812–820

    PubMed  CAS  Google Scholar 

  93. Ten Hove T, Corbaz A, Amitai H, Aloni S, Belzer I, Graber P, Drillenburg P, van Deventer SJ, Chvatchko Y, Te Velde AA (2001) Blockade of endogenous IL-18 ameliorates TNBS-induced colitis by decreasing local TNF-alpha production in mice. Gastroenterology 121: 1372–1379

    PubMed  Google Scholar 

  94. Wirtz S, Becker C, Blumberg R, Galle PR, Neurath MF (2002) Treatment of T cell-dependent experimental colitis in SCID mice by local administration of an adenovirus expressing IL-18 antisense mRNA. J Immunol 168: 411–420

    PubMed  CAS  Google Scholar 

  95. Smeets RL, van de Loo FA, Arntz OJ, Bennink MB, Joosten LA, van den Berg WB (2003) Adenoviral delivery of IL-18 binding protein C ameliorates collagen-induced arthritis in mice. Gene Ther 10: 1004–1011

    PubMed  CAS  Google Scholar 

  96. Maecker HT, Hansen G, Walter DM, DeKruyff RH, Levy S, Umetsu DT (2001) Vaccination with allergen-IL-18 fusion DNA protects against, and reverses established, airway hyperreactivity in a murine asthma model. J Immunol 166: 959–965

    PubMed  CAS  Google Scholar 

  97. Im SH, Barchan D, Maiti PK, Raveh L, Souroujon MC, Fuchs S (2001) Suppression of experimental myasthenia gravis, a B cell-mediated autoimmune disease, by blockade of IL-18. FASEB J 15: 2140–2148

    PubMed  CAS  Google Scholar 

  98. Furlan R, Martino G, Galbiati F, Poliani PL, Smiroldo S, Bergami A, Desina G, Comi G, Flavell R, Su MS et al (1999) Caspase-1 regulates the inflammatory process leading to autoimmune demyelination. J Immunol 163: 2403–2409

    PubMed  CAS  Google Scholar 

  99. Faggioni R, Jones-Carson J, Reed DA, Dinarello CA, Feingold KR, Grunfeld C, Fantuzzi G (2000) Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity: Role of tumor necrosis factor alpha and IL-18. Proc Natl Acad Sci USA 97: 2367–2372

    PubMed  CAS  Google Scholar 

  100. Fantuzzi G, Banda NK, Guthridge C, Vondracek A, Kim SH, Siegmund B, Azam T, Sennello JA, Dinarello CA, Arend WP (2003) Generation and characterization of mice transgenic for human IL-18-binding protein isoform a. J Leukoc Biol 74: 889–896

    PubMed  CAS  Google Scholar 

  101. Tsutsui H, Kayagaki N, Kuida K, Nakano H, Hayashi N, Takeda K, Matsui K, Kashiwamura S, Hada T, Akira S et al (1999) Caspase-1-independent, Fas/Fas ligand-mediated IL-18 secretion from macrophages causes acute liver injury in mice. Immunity 11: 359–367

    PubMed  CAS  Google Scholar 

  102. Fantuzzi G, Reed DA, Dinarello CA (1999) IL-12-induced IFNγ is dependent on caspase-1 processing of the IL-18 precursor. J Clin Invest 104: 761–767

    PubMed  CAS  Google Scholar 

  103. Netea MG, Fantuzzi G, Kullberg BJ, Stuyt RJ, Pulido EJ, McIntyre RC Jr, Joosten LA, Van der Meer JW, Dinarello CA (2000) Neutralization of IL-18 reduces neutrophil tissue accumulation and protects mice against lethal Escherichia coli and Salmonella typhimurium endotoxemia. J Immunol 164: 2644–2649

    PubMed  CAS  Google Scholar 

  104. Vidal-Vanaclocha F, Fantuzzi G, Mendoza L, Fuentes AM, Anasagasti MJ, Martin J, Carrascal T, Walsh P, Reznikov LL, Kim SH et al (2000) IL-18 regulates IL-1 beta-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1. Proc Natl Acad Sci USA 97: 734–739

    PubMed  CAS  Google Scholar 

  105. Takeuchi D, Yoshidome H, Kato A, Ito H, Kimura F, Shimizu H, Ohtsuka M, Morita Y, Miyazaki M (2004) Interleukin 18 causes hepatic ischemia/reperfusion injury by suppressing anti-inflammatory cytokine expression in mice. Hepatology 39: 699–710

    PubMed  CAS  Google Scholar 

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  1. Department of Medicine, Division of Infectious Diseases, University of Colorado Denver, 12700 East 19th Ave, B168, Aurora, CO, 80045, USA

    Charles A. Dinarello

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  1. Charles A. Dinarello
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  1. Division of Clinical Immunology and Rheumatology EULAR & FOCIS Center of Excellence Academic Medical Center, University of Amsterdam, Meibergdreef 9, Room F4-218, 1105, AZ Amsterdam, The Netherlands

    Paul-Peter Tak

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Dinarello, C.A. (2009). Role of IL-18 in inflammatory diseases. In: Tak, PP. (eds) New Therapeutic Targets in Rheumatoid Arthritis. Progress in Inflammation Research. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-8238-4_7

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  • DOI: https://doi.org/10.1007/978-3-7643-8238-4_7

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