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2016 | 63 | 1 | 59-63
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Interleukin 18 (IL-18) as a target for immune intervention

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Interleukin 18 (IL-18) is a pleiotropic cytokine involved in the regulation of innate and acquired immune response. In the milieu of IL-12 or IL-15, IL-18 is a potent inducer of IFN-gamma in natural killer (NK) cells and CD4 T helper (Th) 1 lymphocytes. However, IL-18 also modulates Th2 and Th17 cell responses, as well as the activity of CD8 cytotoxic cells and neutrophils, in a host microenvironment-dependent manner. It is produced by various hematopoietic and nonhematopoietic cells, including dendritic cells and macrophages. In an organism, bioactivity of the cytokine depends on the intensity of IL-18 production, the level of its natural inhibitory protein - IL-18BP (IL-18 binding protein) and the surface expression of IL-18 receptors (IL-18R) on the responding cells. This review summarizes the biology of the IL-18/IL-18BP/IL-18R system and its role in the host defense against infections. The prospects for IL-18 application in immunotherapeutic or prophylactic interventions in infectious and non-infectious diseases are discussed.
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  • Division of Cellular Immunology, Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, University of Lodz, Łódź, Poland
  • Division of Cellular Immunology, Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, University of Lodz, Łódź, Poland
  • Division of Cellular Immunology, Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, University of Lodz, Łódź, Poland
  • Division of Cellular Immunology, Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, University of Lodz, Łódź, Poland
  • Biet F, Kremer L, Wolowczuk I, Delacre M, Locht C (2002) Mycobacterium bovis BCG producing interleukin-18 increases antigen-specific gamma interferon production in mice. Infect Immun 70: 6549-6557.
  • Biet F, Duez C, Kremer L, Marquillies P, Amniai L, Tonnel AB, Locht C, Pestel J (2005) Recombinant Mycobacterium bovis BCG producing IL-18 reduces IL-5 production and bronchoalveolar eosinophilia induced by an allergic reaction. Allergy 60: 1065-1072.
  • Diakowska D, Markocka-Maczka K, Grabowski K, Lewandowski A (2006) Serum interleukin-12 and interleukin-18 levels in patients with oesophageal squamous cell carcinoma. Exp Oncol 28: 319-322.
  • Dinarello C, Fantuzzi G (2003) Interleukin-18 and host defense against infection. J Infect Dis 187: S370-S384.
  • Dinarello CA, Novick D, Kim S, Kaplanski G (2013) Interleukin-18 and IL-18 binding protein. Front Immunol 4: 289.
  • Fabbi M, Carbotti G, Ferrini S (2015) Context-dependent role of IL-18 in cancer biology and counter-regulation by IL-18BP. J Leukoc Biol 97: 665-675.
  • Gracie JA, Robertson SE, McInnes IB (2003) Interleukin-18. J Leukoc Biol 73: 213-224.
  • Harishankar M, Selvaraj P, Rajeswari DN, Anand SP, Narayanan PR (2007) Promoter polymorphism of IL-18 gene in pulmonary tuberculosis in South Indian population. Int J Immunogenet 34: 317-320.
  • Kalina U, Ballas K, Koyama N, Kauschat D, Miething C, Arnemann J, Martin H, Hoelzer D, Ottmann OG (2000) Genomic organization and regulation of the human interleukin-18 gene. Scand J Immunol 52: 525-530.
  • Kinjo Y, Kawakami K, Uezu K, Yara S, Miyagi K, Koguchi Y, Hoshino T, Okamoto M, Kawase Y, Yokota K, Yoshino K, Takeda K, Akira S, Saito A (2002) Contribution of IL-18 to Th1 response and host defense against infection by Mycobacterium tuberculosis: a comparative study with IL-12p40. J Immunol 169: 323-329.
  • Kinoshita M, Seki S, Ono S, Shinomiya N, Hiraide H (2004) Paradoxical effect of IL 18 therapy on the severe and mild Escherichia coli infections in burn-injured mice. Ann Surg 240: 313-320.
  • Kinoshita M, Kuranaga N, Matsumoto A, Ono S, Shinomiya N, Hiraide H, Seki S (2006) Multiple interleukin-18 injections promote both mouse Th1 and Th2 responses after sublethal Escherichia coli infection. Clin Exp Immunol 143: 41-49.
  • Kinoshita M, Shinomiya N, Ono S, Tsujimoto H, Kawabata T, Matsumoto A, Hiraide H, Seki S (2006) Restoration of natural IgM production from liver B cells by exogenous IL-18 improves the survival of burn-injured mice infected with Pseudomonas aeruginosa. J Immunol 177: 4627-4635.
  • Kinoshita M, Miyazaki H, Ono S, Inatsu A, Nakashima H, Tsujimoto H, Shinomiya N, Saitoh D, Seki S (2011) Enhancement of neutrophil function by interleukin-18 therapy protects burn-injured mice from methicillin-resistant Staphylococcus aureus. Infect Immun 79: 2670-2680.
  • Kinoshita M, Miyazaki H, Ono S, Seki S (2013) Immunoenhancing therapy with interleukin-18 against bacterial infection in immunocompromised hosts after severe surgical stress. J Leukoc Biol 93: 689-698.
  • Kowalski ML, Makowska JS (2015) Seven steps to the diagnosis of NSAIDs hypersensitivity: how to apply a new classification in real practice? AAIR 7: 312-320.
  • Lebel-Binay S, Berger A, Zinzindohoué F, Cugnenc P, Thiounn N, Fridman WH, Pagès F (2000) Interleukin-18: biological properties and clinical implications. Eur Cytokine Netw 11: 15-26.
  • Li DD, Jia LQ, Guo SJ, Shen YC, Wen FQ (2013) Interleukin-18 promoter gene -607C/A polymorphism and tuberculosis risk: a meta-analysis. Chin Med J 126: 3360-3363.
  • Lim HX, Hong HJ, Jung MY, Cho D, Kim TS (2013) Principal role of IL-12p40 in the decreased Th1 and Th17 responses driven by dendritic cells of mice lacking IL-12 and IL 18. Cytokine 63: 179-186.
  • Luo Y, Yamada H, Chen X, Ryan AA, Evanoff DP, Triccas JA, O'Donnell MA (2004) Recombinant Mycobacterium bovis bacillus Calmette-Guérin (BCG) expressing mouse IL-18 augments Th1 immunity and macrophage cytotoxicity. Clin Exp Immunol 137: 24-34.
  • Nakahira M, Ahn HJ, Park WR, Gao P, Tomura M, Park CS, Hamaoka T, Ohta T, Kurimoto M, Fujiwara H (2002) Synergy of IL-12 and IL-18 for IFN-gamma gene expression: IL-12 induced STAT4 contributes to IFN-gamma promoter activation by up-regulating the binding activity of IL-18-induced activator protein 1. J Immunol 168: 1146-1153.
  • Nakamura K, Okamura H, Wada M, Nagata K, Tamura T (1989) Endotoxin-induced serum factor that stimulates gamma interferon production. Infect Immun 57: 590-595.
  • 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.
  • Novick D, Kim S, Kaplanski G, Dinarello CA (2013) Interleukin-18, more than a Th1 cytokine. Semin Immunol 25: 439-448.
  • Okamura H, Tsutsi H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, Torigoe K, Okura T, Nukada Y, Hattori K, Akita K, Namba M, Tanabe F, Konishi K, Fukuda S, Kurimoto M (1995) Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 378: 88-91.
  • Okamoto M, Kato S, Oizumi K, Kinoshita M, Inoue Y, Hoshino K, Akira S, McKenzie AN, Young HA, Hoshino T (2002) Interleukin 18 (IL-18) in synergy with IL-2 induces lethal lung injury in mice: a potential role for cytokines, chemokines, and natural killer cells in the pathogenesis of interstitial pneumonia. Blood 99: 1289-1298.
  • Okazawa A, Kanai T, Nakamaru K, Sato T, Inoue N, Ogata H, Iwao Y, Ikeda M, Kawamura T, Makita S, Uraushihara K, Okamoto R, Yamazaki M, Kurimoto M, Ishii H, Watanabe M, Hibi T (2004) Human intestinal epithelial cell-derived interleukin (IL)-18, along with IL-2, IL-7 and IL-15, is a potent synergistic factor for the proliferation of intraepithelial lymphocytes. Clin Exp Immunol 136: 269-276.
  • Robertson MJ, Kirkwood JM, Logan TF (2008) A dose-escalation study of recombinant human interleukin-18 using two different schedules of administration in patients with cancer. Clin Cancer Res 14: 3462-3469.
  • Robinson CM, Jung JY, Nau GJ (2012) Interferon-γ, tumor necrosis factor, and interleukin-18 cooperate to control growth of Mycobacterium tuberculosis in human macrophages. Cytokine 60: 233-241.
  • Schneider BE, Korbel D, Hagens K, Koch M, Raupach B, Enders J, Kaufmann SH, Mittrucker HW, Schaible UE (2010) A role for IL-18 in protective immunity against Mycobacterium tuberculosis. Eur J Immunol 40: 396-405.
  • Srivastava S, Pelloso D, Feng H, Voiles L, Lewis D, Haskova Z, Whitacre M, Trulli S, Chen YJ, Toso J, Jonak ZL, Chang HC, Robertson MJ (2013) Effects of interleukin-18 on natural killer cells: costimulation of activation through Fc receptors for immunoglobulin. Cancer Immunol Immunother 62: 1073-1082.
  • Szpakowski P, Biet F, Locht C, Paszkiewicz M, Rudnicka W, Druszczynska M, Allain F, Fol M, Pestel J, Kowalewicz-Kulbat M (2015) Dendritic cell activity driven by recombinant Mycobacterium bovis BCG producing human IL-18, in healthy BCG vaccinated adults. J Immunol Res 2015: 359153.
  • Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM (2006) Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24: 677-688.
  • Wei H, Wang D, Qian Y, Liu X, Fan S, Yin HS, Wang X (2014) Structural basis for the specific recognition of IL-18 by its alpha receptor. FEBS Lett 588: 3838-3843.
  • World Health Organization. Global tuberculosis report 2014.
  • Zhang J, Zheng L, Zhu D, An H, Yang Y, Liang Y, Zhao W, Ding W, Wu X (2014) Polymorphisms in the interleukin 18 receptor 1 gene and tuberculosis susceptibility among Chinese. PLoS ONE 9: e110734.
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