Abstract
Interleukin (IL)-18, structurally similar to IL-1-, is a member of IL-1 superfamily of cytokines. This cytokine, which is expressed by many human lymphoid and nonlymphoid cells, has an important role in inflammatory processes. The main function of IL-18 is mediated through induction of interferon-γ (IFN-γ) secretion from T helper (Th1) cells. This cytokine synergistically with IL-12 contributes to Th1 differentiation and, therefore, is important in host defense mechanisms against intracellular bacteria, viruses, and fungi. Recent evidences showing the involvement of IL-18 in Th2 differentiation and ultimately IgE production from B cells have shed a new insight on the dual effects of IL-18 on Th1 and Th2 inflammatory responses. IL-18 in combination with IL-12 can activate cytotoxic T cells (CTLs), as well as natural killer (NK) cells, to produce IFN-γ and, therefore, may contribute to tumor immunity. The biological activity of IL-18 is not limited to these cells, but it also plays a role in development of Th17 cell responses. IL-18 synergistically with IL-23 can induce IL-17 secretion from Th17 cells. The diverse biological activity of IL-18 on T-cell subsets and other immune cells has made this cytokine a good target for investigating its role in various inflammatory-based diseases. Lately, the discovery of IL-18 binding protein (IL- 18BP), a physiological inhibitor of IL-18 and a hallmark of IL-18 biology, made this cytokine an attractive target for studying its pros and cons in the treatment of various diseases. In recent years, the biology, genetics, and pathological role of IL-18 have been studied in a number of diseases. In this article, we aimed to present an updated review on these aspects regarding the contribution of IL-18 to important diseases such as cancer, autoimmunity, and inflammatory-mediated conditions including allergic diseases, metabolic syndrome, and atherosclerosis. Emerging data indicating prognostic, diagnostic, and therapeutic features of IL-18 and its related molecules will also be discussed.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Okamura H, Nagata K, Komatsu T, et al. A novel costimulatory factor for gamma interferon induction found in the livers of mice causes endotoxic shock. Infect Immun 1995; 63: 3966.
Ghayur T, Banerjee S, Hugunin M, et al. Caspase-1processes IFNgamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature 1997; 386: 619.
Dinarello CA. Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. AmJ Clin Nutr 2006; 83: 447S.
Dinarello CA, Novick D, Kim S, Kaplanski G. Interleukin-18 and IL-18 binding protein. Front Immunol 2013; 4: 289.
Turner MD, Nedjai B, Hurst T, Pennington DJ. Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta 2014; 1843: 2563.
Nakahira M, Ahn HJ, Park WR, et al. Synergy of IL-12 and IL-18 for IFN-gamma gene expression: IL-12-induced STAT4 contributes to IFN-gamma promoter activation by up-regulatingthe binding activity of IL-18-induced activator protein 1. J Immunol 2002; 168: 1146.
Okamura H, Kashiwamura S, Tsutsui H, Yoshimoto T, Nakanishi K. Regulation of interferon-gamma production by IL-12 and IL-18. Curr Opin Immunol 1998; 10: 259.
Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 is a uniquecytokine that stimulates both Th1 and Th2 responses depending on its cytokinemilieu. Cytokine Growth Factor Rev 2001; 12: 53.
Kawayama T, Okamoto M, Imaoka H, Kato S, Young HA, Hoshino T. Interleukin-18in pulmonary inflammatory diseases. J Interferon Cytokine Res 2012; 32: 443.
Nakanishi K. Regulation of Th1 and Th2 immune responses by IL-18. Kekkaku 2002; 77: 87.
Yoshimoto T, Nakanishi K. Roles of IL-18 in basophils and mast cells. Allergol Int 2006; 55: 105.
Wawrocki S, Druszczynska M, Kowalewicz-Kulbat M, Rudnicka W. Interleukin 18(IL-18) as a target for immune intervention. Acta Biochim Pol 2016; 63: 59.
Biet F, Locht C, Kremer L. Immunoregulatory functions of interleukin 18 andits role in defense against bacterial pathogens. J Mol Med (Berl) 2002; 80: 147.
Vidal-Vanaclocha F, Mendoza L, Telleria N, et al. Clinical and experimentalapproaches to the pathophysiology of interleukin-18 in cancer progression. Cancer Metastasis Rev 2006; 25: 417.
Novick D, Kim SH, Fantuzzi G, Reznikov LL, Dinarello CA, Rubinstein M. Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. Immunity 1999; 10: 127.
Mühl H, Kämpfer H, Bosmann M, Frank S, Radeke H, Pfeilschifter J. Interferon-gamma mediates gene expression of IL-18 binding protein in nonleukocytic cells. Biochem Biophys Res Commun 2000; 27: 960.
Fabbi M, Carbotti G, Ferrini S. Context-dependent role of IL-18 in cancerbiology and counter-regulation by IL-18BP. J LeukocBiol 2015; 97: 665.
Palma G, Barbieri A, Bimonte S, et al. Interleukin 18: friend or foe in cancer. Biochim Biophys Acta 2013; 1836: 296.
Tran LS, Chonwerawong M, Ferrero RL. Regulation and functions of inflammasome-mediated cytokines in Helicobacter pylori infection. Microbes Infect 2017; 19: 449–58.
Oertli M, Sundquist M, Hitzler I, et al. DC-derived IL-18 drives Treg differentiation, murine Helicobacter pylori-specific immune tolerance, and asthma protection. J Clin Invest 2012; 122: 1082.
Hitzler I, Sayi A, Kohler E, et al. Caspase-1has both proinflammatory and regulatory properties in Helicobacter infections, which are differentially mediated by its substrates IL-1and IL-18. J Immunol 2012; 188: 3594.
Tas F, Tilgen Yasasever C, Karabulut S, Tastekin D, Duranyildiz D. Clinicalsignificance of serum interleukin-18 (IL-18) levels in patients with gastriccancer. Biomed Pharmacother 2015; 70: 19.
Matveeva LV, Mosina LM. Serum interleukin-18 level in precancerous conditionsand gastric cancer. Eksp Klin Gastroenterol 2013; 6: 21–4.
Haghshenas MR, Hosseini SV, Mahmoudi M, Saberi-Firozi M, Farjadian S, Ghaderi A. IL-18 serum level and IL-18 promoter gene polymorphism in Iranian patientswith gastrointestinal cancers. J Gastroenterol Hepatol 2009; 24: 1119.
Kim J, Kim C, Kim TS, et al. IL-18 enhances thrombospondin-1 production in human gastric cancer via JNK pathway. Biochem Biophys Res Commun 2006; 344: 1284.
Kang JS, Bae SY, Kim HR, et al. Interleukin-18 increases metastasis and immuneescape of stomach cancer via the downregulation of CD70 and maintenance of CD44. Carcinogenesis 2009; 30: 1987.
Pagès F, Berger A, Henglein B, et al. Modulation of interleukin-18 expression in human coloncarcinoma: consequences for tumor immune surveillance. Int J Cancer 1999; 84: 326.
Wen Z, Ouyang Q, Chen D, Su X. Interleukin 18 expression in colon cancer andadenoma. Sichuan Da Xue Xue Bao Yi Xue Ban 2003; 34: 262.
Salcedo R, Worschech A, Cardone M, et al. MyD88-mediated signaling prevents development ofadenocarcinomas of the colon: role of interleukin 18. J Exp Med 2010; 207: 1625.
Zaki MH, Vogel P, Body-Malapel M, Lamkanfi M, Kanneganti TD. IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumorformation. J Immunol 2010; 185: 4912.
Yang C, Cao H, Liu N, Xu K, Ding M, Mao LJ. Oncolytic adenovirus expressing Interleukin-18 improves antitumor activity of dacarbazine for malignant melanoma. Drug Des Devel Ther 2016; 10: 3755.
Coughlin CM, Salhany KE, Wysocka M, et al. Interleukin-12 and interleukin-18 synergisticallyinduce murine tumor regression which involves inhibition of angiogenesis. J Clin Invest 1998; 101: 1441.
Nagai H, Hara I, Horikawa T, Oka M, Kamidono S, Ichihashi M. Gene transfer of secreted-type modified interleukin-18 gene to B16F10 melanoma cells suppresses in vivo tumor growth through inhibition of tumor vessel formation. J Invest Dermatol 2002; 119: 541.
Loeffler M, Le’Negrate G, Krajewska M, Reed JC. IL-18-producing Salmonella inhibit tumor growth. Cancer Gene Ther 2008; 15: 787.
Nishio S, Yamada N, Ohyama H, et al. Enhanced suppression of pulmonary metastasis of malignant melanoma cells by combined administration of alpha-galactosylceramide and interleukin-18. Cancer Sci 2008; 99: 113.
Ni J, Miller M, Stojanovic A, Garbi N, Cerwenka A. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. J Exp Med 2012; 209: 2351.
Choi IK, Lee JS, Zhang SN, et al. Oncolytic adenovirus coexpressing IL-12 and IL-18 improves tumor-specific immunity via differentiation of T cells expressing IL-12Rβ2 or IL-18Rα. Gene Ther 2011; 18: 898.
Terme M, Ullrich E, Aymeric L, et al. IL-18 induces PD-1-dependentimmunosuppression in cancer. Cancer Res 2011; 71: 5393.
Carrascal MT, Mendoza L, Valcárcel M, et al. Interleukin-18 binding protein reduces b16 melanoma hepatic metastasis by neutralizing adhesiveness and growth factors of sinusoidal endothelium. Cancer Res 2003; 63: 491.
Asakawa M, Kono H, Amemiya H, et al. Role ofinterleukin-18 and its receptor in hepatocellular carcinoma associated withhepatitis C virus infection. Int J Cancer 2006; 118: 564.
Mohran ZY, Ali-Eldin FA, Abdel Aal HA. Serum interleukin-18: does it have a role in the diagnosis of hepatitis C virus related hepatocellular carcinoma? Arab J Gastroenterol 2011; 12: 29.
Wang ZY, Gaggero A, Rubartelli A, et al. Expression of interleukin-18 in human ovarian carcinoma and normal ovarian epithelium: evidence for defective processing in tumor cells. Int J Cancer 2002; 98: 873.
Medina L, Rabinovich A, Piura B, Dyomin V, Levy RS, Huleihel M. Expression of IL-18, IL-18 binding protein, and IL-18 receptor by normal and cancerous human ovarian tissues: possible implication of IL-18 in the pathogenesis of ovarian carcinoma. Mediators Inflamm 2014; 2014: 914954.
Giedraitis V, He B, Huang WX, Hillert J. Cloning and mutation analysis of the human IL-18 promoter: a possible role of polymorphisms in expression regulation. J Neuroimmunol 2001; 112: 146.
Liang TJ, Ma H, Wang CX, Liu YR, Wang XG. The-137G>C polymorphism in interleukin-18 promoter region and cancer risk: evidence from a meta-analysis of 21 studies. Tumour Biol 2013; 34: 3483.
Mi YY, Yu QQ, Yu ML, et al. Reviewand pooled analysis of studies on-607(C/A) and-137(G/C) polymorphisms in IL-18 and cancer risk. Med Oncol 2011; 28: 1107.
Li X, Ren D, Li Y, Xu J, Liu C, Zhao Y. Increased cancer risk associated with the-607C/A polymorphism in interleukin-18 gene promoter: an updated meta-analysis including 12,502 subjects. J BUON 2015; 20: 902.
Wang M, Zhu XY, Wang L, Lin Y. The-607C/A polymorphisms in interleukin-18 gene promoter contributes to cancer risk: evidence from a meta-analysis of 22 case-control studies. PLoS One 2013; 8: e76915.
Yang X, Qiu MT, Hu JW, et al. Association of interleukin-18 gene promoter-607 C>A and-137G>C polymorphisms with cancer risk: a meta-analysis of 26 studies. PLoS One 2013; 8: e73671.
Yao J, Li ZH, Li YX, et al. Association between the-607 C >A polymorphism in interleukin-18 gene promoter with gastrointestinal cancer risk: a meta-analysis. Genet Mol Res 2015; 14: 16880.
Zhu SL, Zhao Y, Hu XY, et al. Genetic polymorphisms-137 (rs187238) and-607 (rs1946518) in the interleukin-18 promoter may not be associated with development of hepatocellular carcinoma. Sci Rep 2016; 6: 39404.
Lau HK, Hsieh MJ, Yang SF, et al. Association between interleukin-18 polymorphisms and hepatocellular carcinoma occurrence and clinical progression. Int J Med Sci 2016; 13: 556.
Dai ZJ, Liu XH, Wang M, et al. IL-18 polymorphisms contribute to hepatitisBvirus-related cirrhosis and hepatocellular carcinoma susceptibility in Chinese population: a case-control study. Oncotarget 2017; 8: 81350–60.
Bao J, Lu Y, Deng Y, et al. Association between IL-18 polymorphisms, serum levels and HBV-related hepatocellularcarcinoma in a Chinese population: a retrospective case-control study. Cancer Cell Int 2015; 15: 72.
Guo XG, Xia Y. The interleukin-18 promoter-607C>A polymorphism contributes tonasopharyngeal carcinoma risk: evidence from a meta-analysis including 1,886 subjects. Asian Pac J Cancer Prev 2013; 14: 7577.
Nong LG, Luo B, Zhang L, Nong HB. Interleukin-18 gene promoter polymorphismand the risk of nasopharyngeal carcinoma in a Chinese population. DNA Cell Biol 2009; 28: 507.
Pratesi C, Bortolin MT, Bidoli E, et al. Interleukin-10 and interleukin-18 promoter polymorphisms in an Italian cohort of patients with undifferentiated carcinoma of nasopharyngeal type. Cancer Immunol Immunother 2006; 55: 23.
Singh PK, Ahmad MK, Kumar V, et al. Effects of interleukin-18 promoter (C607A and G137C) gene polymorphisms and their association with oral squamous cell carcinoma (OSCC) innorthern India. Tumour Biol 2014; 35: 12275.
Farhat K, Hassen E, Bouzgarrou N, Gabbouj S, Bouaouina N, Chouchane L. Functional IL-18 promoter gene polymorphisms in Tunisian nasopharyngeal carcinoma patients. Cytokine 2008; 43: 132.
Back LK, Farias TD, da Cunha PA, et al. Functional polymorphisms of interleukin-18 gene and risk ofbreast cancer in a Brazilian population. Tissue Antigens 2014; 84: 229.
Khalili-Azad T, Razmkhah M, Ghiam AF, et al. Association of interleukin-18 gene promoter polymorphisms with breast cancer. Neoplasma 2009; 56: 22.
Taheri M, Hashemi M, Eskandari-Nasab E, et al. Association of-607 C/A polymorphism of IL-18 gene(rs1946518) with breast cancer risk in Zahedan, Southeast Iran. Prague Med Rep 2012; 113: 217.
Jurecekova J, Babusikova E, KmetovaSivonova M, et al. Association between interleukin-18 variants and prostate cancer in Slovak population. Neoplasma 2017; 64: 148.
Liu JM, Liu JN, Wei MT, et al. Effect of IL-18 gene promoter polymorphisms on prostate cancer occurrence and prognosis in Han Chinese population. Genet Mol Res 2013; 12: 820.
Liu Y, Lin N, Huang L, Xu Q, Pang G. Genetic polymorphisms of the interleukin-18 gene and risk of prostate cancer. DNA Cell Biol 2007; 26: 613.
Bushley AW, Ferrell R, McDuffie K, et al. Polymorphisms of interleukin (IL)-1alpha, IL-1beta, IL-6, IL-10, and IL-18 and the risk of ovarian cancer. Gynecol Oncol 2004; 95: 672.
Samsami Dehaghani A, Shahriary K, Kashef MA,et al. Interleukin-18 gene promoter and serum level in women with ovarian cancer. Mol Biol Rep 2009; 36: 2393.
Abdolahi F, Dabbaghmanesh MH, Haghshenas MR, Ghaderi A, Erfani N. A gene-disease association study of IL18 in thyroid cancer: genotype and haplotype analyses. Endocrine 2015; 50: 698.
Farjadfar A, Mojtahedi Z, Ghayumi MA, Erfani N, Haghshenas MR, Ghaderi A. Interleukin-18 promoter polymorphism is associated with lung cancer: a case-control study. Acta Oncol 2009; 48: 971.
Harms RZ, Yarde DN, Guinn Z, et al. Increased expression of IL-18 in the serum and islets of type 1 diabetics. Mol Immunol 2015; 64: 306.
Nicoletti F, Conget I, Di Marco R, et al. Serum levels of the interferon gamma-inducing cytokine interleukin-18 are increased in individuals at high risk of developing type I diabetes. Diabetologia 2001; 44: 309.
Martinez-Hervas S, Martínez-Barquero V, Nu˜nezSavall E, et al. Plasma IL-18 levels are related to insulin and are modulated by IL-18 gene polymorphisms. Clin Investig Arterioscler 2015; 27: 265.
Katakami N, Kaneto H, Matsuhisa M, et al. Serum interleukin-18 levels are increased and closely associated with various soluble adhesion molecule levels in type 1 diabetic patients. Diabetes Care 2007; 30: 159.
Kuryliszyn-Moskal A, Dubicki A, Zarzycki W, Zonnenberg A, Gorska M. Microvascular abnormalities in capillaroscopy correlate with higher serum IL-18 and sE-selectin levels in patients with type 1 diabetes complicated by microangiopathy. Folia Histochem Cytobiol 2011; 49: 104.
Dong G, Liang L, Fu J, Zou C. Serum interleukin-18 levels are raised in diabetic ketoacidosis in Chinese children with type 1 diabetes mellitus. Indian Pediatr 2007; 44: 732.
Sedimbi SK, Hägglöf T, Karlsson MC. IL-18 in inflammatory and autoimmune disease. Cell Mol Life Sci 2013; 70: 4795.
Hong TP, Andersen NA, Nielsen K, et al. 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 2000; 11: 193.
Marleau AM, Sarvetnick NE. IL-18 is required for self-reactive T cell expansion in NOD mice. J Autoimmun 2011; 36: 263.
Zaccone P, Phillips J, Conget I, Cooke A, Nicoletti F. IL-18 binding protein fusion construct delays the development of diabetes in adoptive transfer and cyclophosphamide-induced diabetes in NOD mouse. Clin Immunol 2005; 115: 74.
Lee YH, Kim JH, Song GG. Interleukin-18 promoter-607 C/A and-137 G/C polymorphisms and susceptibility to type 1 diabetes: A meta-analysis. Hum Immunol 2015; 76: 537.
Hadžija MP, Korolija M, Jemin N, et al. Polymorphisms in the IL-18 and IL-12B genes and their association with the clinical outcome in Croatian patients with Type 1 diabetes. Gene 2013; 512: 477.
Altinova AE, Engin D, Akbay E, et al. Association of polymorphisms in the IL-18 and IL-12 genes with susceptibility to Type 1 diabetes in Turkish patients. J Endocrinol Invest 2010; 33: 451.
Dong GP, Yu ZS, Liang L, Zou CC, Fu JF, Wang CL. IL-18 gene promoter-137C/G and-607C/A polymorphisms in Chinese Han children with type 1 diabetes mellitus. Int J Immunogenet 2007; 34: 75.
Mojtahedi Z, Naeimi S, Farjadian S, Omrani GR, Ghaderi A. Association of IL-18 promoter polymorphisms with predisposition to Type 1 diabetes. Diabet Med 2006; 23: 235.
Chen YC, Chen SD, Miao L, et al. Serum levels of interleukin (IL)-18, IL-23 and IL-17 in Chinese patients with multiple sclerosis. J Neuroimmunol 2012; 243: 56.
Furlan R, Filippi M, Bergami A, et al. Peripheral levels of caspase-1 mRNA correlate with disease activity in patients with multiple sclerosis; a preliminary study. J Neurol Neurosurg Psychiatry 1999; 67: 785.
Karakas Celik S, Öz ZS, Dursun A, et al. Interleukin 18 gene polymorphism is a risk factor for multiple sclerosis. Mol Biol Rep 2014; 41: 1653.
Orhan G, Eruyar E, Mungan SÖ E, Ak F, Karahalil B. The association of IL-18 gene promoter polymorphisms and the levels of serum IL-18 on the risk of multiple sclerosis. Clin Neurol Neurosurg 2016; 146: 96.
Sato M, Takemura M, Shinohe R, Koishi H, Morita T, Seishima M. Clinical significance of serum IL-18 determination in rheumatoid arthritis. Rinsho Byori 2004; 52: 109.
Wei XQ, Leung BP, Arthur HM, McInnes IB, Liew FY. Reduced incidence and severity of collagen-induced arthritis in mice lacking IL-18. J Immunol 2001; 166: 517.
Haas CS, Amin MA, Allen BB, et al. Inhibition of angiogenesis by interleukin-4 gene therapy in rat adjuvant-induced arthritis. Arthritis Rheum 2006; 54: 2402.
Volin MV, Koch AE. Interleukin-18: a mediator of inflammation and angiogenesis in rheumatoid arthritis. J Interferon Cytokine Res 2011; 31: 745.
Li LL, Deng XF, Li JP, Ning N, Hou XL, Chen JL. Association of IL-18 polymorphisms with rheumatoid arthritis: a meta-analysis. Genet Mol Res 2016; 22: 15.
Cai LP, Zhou LJ, Lu SY, et al. Association of IL-18 promoter gene polymorphisms with rheumatoid arthritis: a meta-analysis. Mol Biol Rep 2014; 41: 8211.
Favilli F, Anzilotti C, Martinelli L, et al. IL-18 activity in systemic lupus erythematosus. Ann N Y Acad Sci 2009; 1173: 301.
Boraschi D, Dinarello CA. IL-18 in autoimmunity: review. Eur Cytokine Netw 2006; 17: 224.
Aghdashi M, Aribi S, Salami S. Serum levels of IL-18 in Iranian females with systemic lupus erythematosus. Med Arch 2013; 67: 237.
Song GG, Choi SJ, Ji JD, Lee YH. Association between interleukin-18polymorphisms and systemic lupus erythematosus: a meta-analysis. Mol Biol Rep 2013; 40: 2581.
Fouad NA, Baraka EA, Hassan WA. Interleukin-18 gene polymorphisms in systemic lupus erythematosus: relation to disease status. Egypt J Immunol 2014; 21: 1.
Ludwiczek O, Kaser A, Novick D, Dinarello CA, Rubinstein M, Tilg H. Elevated systemic levels of free interleukin-18 (IL-18) in patients with Crohn’s disease. Eur Cytokine Netw 2005; 16: 27.
Monteleone G, Trapasso F, Parrello T, et al. Bioactive IL-18 expression is up-regulated in Crohn’s disease. J Immunol 1999; 163: 143.
Gao SJ, Zhang L, Lu W, et al. Interleukin-18 genetic polymorphisms contribute differentially to the susceptibility to Crohn’s disease. World J Gastroenterol 2015; 21: 8711.
Ben Aleya W, Sfar I, Habibi I, et al. Interleukin-18 gene polymorphismsin Tunisian patients with inflammatory bowel disease. Digestion 2011; 83: 269.
Sawada M, Kawayama T, Imaoka H, et al. IL-18 induces airway hyper responsiveness and pulmonary inflammation via CD4+ T cell and IL-13. PLoS One 2013; 8: e54623.
Wild JS, Sigounas A, Sur N, et al. IFN-gamma-inducing factor (IL-18) increases allergic sensitization, serum IgE, Th2 cytokines and airway eosinophilia in a mouse model of allergic asthma. J Immunol 2000; 164: 2701.
Rovina N, Dima E, Bakakos P, et al. Low interleukin (IL)-18 levels in sputum supernatants of patients with severe refractory asthma. Respir Med 2015; 109: 580.
Birbian N, Singh J, Jindal SK. Protective role of IL-18-137G/C polymorphismin a North Indian population with asthma: a pilot study. Cytokine 2013; 61: 188.
Shaaban HH, Mohy AM, Abdel-Razek AR, Wahab AA. Interleukin-18-607C/A gene polymorphism in Egyptian asthmatic children. Mol Diagn Ther 2014; 18: 427.
Lachheb J, Chelbi H, Ammar J, Hamzaoui K, Hamzaoui A. Promoter polymorphism ofthe IL-18 gene is associated with atopic asthma in Tunisian children. Int J Immunogenet 2008; 35: 63.
Ma Y, Zhang B, Tang RK, Liu Y, Peng GG. Interleukin-18 promoter polymorphism and asthma risk: a meta-analysis. Mol Biol Rep 2012; 39: 1371.
Cheng D, Hao Y, Zhou W, Ma Y. The relationship between interleukin-18 polymorphisms and allergic disease: a metaanalysis. Biomed Res Int 2014; 2014: 290687.
Grundy SM. Metabolic syndrome: therapeutic considerations. Handb Exp Pharmacol 2005; 170: 107–33.
Pradhan AD, Ridker PM. Do atherosclerosis and type 2 diabetes share a common inflammatory basis? Eur Heart J 2002; 23: 831.
de Oliveira A, Hermsdorff HH, Cocate PG, Santos EC, Bressan J, Natali AJ. Accuracy of plasma interleukin-18 and adiponectin concentrations in predicting metabolic syndrome and cardiometabolic disease risk in middle-age Brazilian men. Appl Physiol Nutr Metab 2015; 40: 1048.
Trøseid M, Seljeflot I, Arnesen H. The role of interleukin-18 in the metabolic syndrome. Cardiovasc Diabetol 2010; 9: 11.
Netea MG, Joosten LA, Lewis E, et al. Deficiency ofinterleukin-18 in mice leads to hyperphagia, obesity and insulin resistance. Nat Med 2006; 12: 650.
Murphy AJ, Kraakman MJ, Kammoun HL, et al. IL-18 Production from the NLRP1 inflammasome prevents obesity and metabolic syndrome. Cell Metab 2016; 23: 155.
Presta I, Andreozzi F, Succurro E, et al. IL-18 gene polymorphism and metabolic syndrome. Nutr Metab Cardiovasc Dis 2009; 19: e5–6.
Mallat Z, Corbaz A, Scoazec A, et al. Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation 2001; 104: 1598.
Jabir NR, Firoz CK, Kamal MA, et al. Assessment of IL-18 serum level and its promoter polymorphisms in the Saudi coronary artery disease (CAD) patients. J Cell Biochem 2017; 118: 1849.
Hernesniemi JA, Karhunen PJ, Rontu R, et al. Interleukin-18 promoter polymorphism associates with the occurrence of sudden cardiac death among Caucasian males: the Helsinki sudden death study. Atherosclerosis 2008; 196: 643.
Ma JB, Chen L, Gao B, Xu J. Effect of polymorphisms in interleukin-18 gene on the susceptibility to coronary artery disease in a Chinese population. Genet Mol Res 2016; 15.
Opstad TB, Pettersen AÅ TB, Arnesen H, Seljeflot I. Circulating levels of IL-18 are significantly influenced by the IL-18 +183 A/G polymorphism in coronary artery disease patients with diabetes type 2 and the metabolic syndrome: an observational study. Cardiovasc Diabetol 2011; 10: 110.
Tiret L, Godefroy T, Lubos E, et al. Genetic analysis of theinterleukin-18 system highlights the role of the interleukin-18 gene in cardiovascular disease. Circulation 2005; 112: 643.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Esmailbeig, M., Ghaderi, A. Interleukin-18: a regulator of cancer and autoimmune diseases. Eur Cytokine Netw 28, 127–140 (2017). https://doi.org/10.1684/ecn.2018.0401
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1684/ecn.2018.0401