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Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii
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4/2011
vol. 28
 
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Review paper
Interleukin 18 – a pleiotropic cytokine involved in the Th1 and Th2 immunological response

Magdalena Trzeciak
,
Małgorzata Sokołowska-Wojdyło
,
Wioletta Barańska-Rybak
,
Agata Maciejewska
,
Igor Michajłowski
,
Jadwiga Roszkiewicz

Post Dermatol Alergol 2011; XXVIII, 4: 309–312
Online publish date: 2011/08/31
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Characteristics

Interleukin 18 (IL-18) was identified in 1989 as the INF-g inducing factor. It was discovered in mouse’s serum, after having injected Propionobacterium acne endotoxin. Six years later, in 1995, IL-18 was cloned and recognized as a single peptide chain of molecular weight 18 000 Da [1, 2]. In the natural environment IL-18 is synthesized as an inactive precursor – polypeptide of molecular weight 24 kDa (pro-IL-18) [3] – and subsequently is activated by intracellular cysteine-caspase 1 protease (enzyme converting IL-1b) [3-5]. Interleukin 18 is secreted by keratinocytes, monocytes, macrophages, dendritic cells, epithelial cells and osteoblasts [4-6]. Moreover, it can be produced by ependymal cells and microglia [7].

Mechanism of action

The receptor for IL-18 is located on numerous cells [2, 6, 8] specified in Table 1. It is a hetero dimer composed of two subunits: a and b. Chain a binds IL-18 and chain β is responsible for the transduction of the signal [1, 2, 4]. The structure of IL-18 receptor and the transduction of the signal are presented in Figure 1.

Binding of IL-18 with the receptor’s a subunit activates β chain and Toll domains located in the cytoplasmic fragment of the chain. The Toll domain binds IL-18 with Toll-like receptor, which recognizes microorganisms’ antigens too. Intracellular protein – MyD88 adapter protein – which is a fragment of the TLR (Toll-like receptor) transduction pathway, is activated and leads to the phosphorylation of protein kinase IRAK (IL-1 receptor-associated kinase), which then activates TRAF 6 protein (TNF-R associated factor 6). Subsequently, through the protein kinase system, which is activated by MAP (mitogen activated protein kinases) mitogen, whose final cascade’s elements include c-Jun N-terminal kinases (JNK), transcription factors activating protein 1 (AP-1) and nuclear factor kB (NFkB) are activated. As a result of this activation, transcription of IL-4, IL-13 and other effectors increases. Furthermore, the increase of the IL-4 and IL-13 concentration, acting through STAT 6, induces allergic inflammation [1, 2, 5, 9, 10].

Interleukin-18 has an additional receptor/inhibitor: IL-18 binding protein (IL-18 BP) [1, 2, 4]. Clinical studies concerning its use in rheumatoid arthritis [2] and psoriasis [2, 11] are ongoing.

Clinical applications

As mentioned before, IL-18 used to be called a factor inducing INF-g from Th, CD8 and NK cells [1, 6, 8, 12, 13]. Considering this activity, IL-18 is a basic cytokine taking part in defence against bacterial, fungal, parasitic and viral infections [3]. It is one of the first to inform the immunological system about emerging infection [4]. Moreover, it was considered that through the induction of INF-g, IL-18 suppress the synthesis of IgE and demonstrates anti-allergic properties. Currently, it is known that it presents such activity in synergy with IL-12 by increasing the expression of IL-18 receptor on T-cells [8, 14].

Breakthrough studies in recent years [3, 4, 6, 14-16] have proved that IL-18 influences the production of IL-4 and IL-13 and, through this, stimulates the synthesis of IgE. Those results have presented IL-18 in a completely different light and have caused a hail of studies on the role of this cytokine in the development of allergic diseases. Interleukin 18 activates T-cells and mastocytes to secrete IL-13 and IL-4 [6, 14, 16]. In combination with IL-2, it increases the production of IL-13 [17]. Besides, what was scientifically proved, in the presence of IL-3 it is able to directly stimulate basophils and mastocytes to secrete inflammatory reaction mediators such as histamine, serotonin, IL-4 and IL-13 without IgE participation. Under the influence of this direct activation, in vitro, basophils produce IL-4 and IL-13, whereas mastocytes produce only IL-13 [6]. It was proved that IL-18 induces skin lesions typical for atopic dermatitis independently of the level of cytokines [16, 18]. A thesis was advanced that it was strictly IL-18, not IgE, that plays a significant role in the development of dermatitis through the activation of mastocytes and T-cells [16]. In transgenic mice, deprived of the STAT6 gene which is responsible for the signal transduction in the development of the allergic reaction and for IgE production, undetectable levels of IgE, and reduced level of histamine and mastocytes were noted. Still, pruritus and skin lesions typical for atopic dermatitis were present in mice. Transgenic mice, deprived of IL-18, did not present any signs of dermatitis, despite the significant level of IgE [16]. Furthermore, it was proved that IL-18 regulates the production of IgE in vivo in the absence of allergens and, in the absence of specific allergens, it is responsible for the induction of atopic phenotype [14, 16].

In summary, IL-18 is a pleiotropic cytokine, which, depending on the environment of cytokines and genetic background, activates a Th1 or Th2 response [3-5, 12-15, 19]. Moreover, Sugama and Conti [7] suggest its neuro--immuno-modulating role and, additionally, its contribution in the control of appetite and obesity development.

Up till now, the contribution of IL-18 in the development of cancer, autoimmune, infectious, inflammatory and allergic diseases has been documented. An elevated level of this cytokine was described in examined patients’ blood serum in the majority of those entities [7, 20-34]. Diseases and conditions proceeding with an increase of IL-18 are presented in Table 2.

The gene of human IL-18 is localized on chromosome 11q22.2-22.3 [5, 9]. Its molecular weight is 20.8 kb [1]. It consists of 6 exons and its expression is controlled by 2 promoters: promoter 1 (exon 1) and promoter 2 (exon 2); the starting codon is localized on exon 2. Of note, chromosome 11q22 has been identified as a gene candidate for atopy [5, 9]. Numerous studies have been performed concerning the relation between the IL-18 gene and diabetes type I, multiple sclerosis, Crohn’s disease, idiopathic arthritis, graft versus host disease (GVHD), and coronary artery disease [1]. In the domain of allergic diseases, a relation between polymorphism of IL-18 gene [1, 38] and polymorphism of IL-18 receptor [39, 40] and pathogenesis of asthma has been confirmed. In a German population of atopic patients, a relation between IL-18 polymorphism and rhinitis has been revealed [9], and in the Czech population, it was suggested that genetic variants of IL-18 may contribute to pathogenesis of allergic rhinitis [34]. German researchers [5] have demonstrated a connection of IL-18 gene polymorphism with high level of IgE and specific hypersensitivity in patients with atopic dermatitis, whereas Korean scientists [3] have described a relation between IL-18 gene polymorphism and allergic type of atopic dermatitis. A relation between the gene’s polymorphism and atopic dermatitis development has also been demonstrated in the Polish population [41].

Conclusions

New genetic and immunological data theoretically indicate the key role of IL-18 in pathogenesis and development of atopic dermatitis. However, that requires further, more extensive clinical studies. Considering the function and mechanisms of action of IL-18 and remembering that this cytokine is tested as a new agent in cancer immunotherapy [42], and its receptor-inhibitor is used in treatment of psoriasis [2, 11] and rheumatoid arthritis [2], we can presume that this cytokine could be a new target in therapy of those diseases and possibly, atopic dermatitis [11].

Despite the knowledge of many functions of IL-18, this cytokine still remains an interesting subject of scientific studies.

References

 1. Thompson SR, Humpheries SE. Interleukin-18 genetics and inflammatory disease susceptibility. Genes Immun 2007; 8: 91-9.  

2. Dinarello CA. Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. Am J Clin Nut 2006; 2: 447-55.

 3. Kim E, Lee JE, Namkung JH, et al. Association of the single nucleotide polymorphism and haplotype of the interleukin 18 gene with atopic dermatitis in Koreans. Clin Exp Allergy 2007; 37: 865-71.

 4. Gołąb J, Jakóbisiak M, Lasek W. Immunologia. Wydawnictwo Naukowe PWN, Warszawa 2002; 219-20.

5. Novak N, Kruse S, Potreck J, et al. Single nucleotide polymorphisms of the IL-18 gene are associated with atopic eczema. Allergy Clin Immunol 2005; 115: 828-33.  

6. Yoshimoto T, Tsutsui H, Tominaga K, et al. IL-18, although antiallergic when administreted with Il-12, stimulates IL-4 and histamine release by basophils. Proc Natl Acad Sci USA 1999; 24: 1362-6.

 7. Sugama S, Conti B. Interleukin 18 and stress. Brain Res Rev 2008; 58: 85-9.  

8. Yoshimoto T, Takeda K, Tanaka T. IL-12 upregulates IL-18 receptor expression on T cells, Th1 cells and B cells: synergism with Il-18 for INFgamma production. J Immunol 1998; 161: 3400-7.

 9. Krause S, Kuehr J, Moseler M, et al. Polymorphisms in the IL-18 gene are associated with specific sensitization to common allergens and allergic rhinitis. J Allergy Clin Immunol 2003; 11: 117-22.

10. Shirakawa T, Deichmann KA, Izuhara K, et al. Atopy and asthma: genetic variants of IL-4 and IL-13 signalling. Immunol Today 2000; 2: 492-9.

11. Numerof RP, Asadullah K. Cytokine and anti-cytokine therapies for psoriasis and atopic dermatitis. Biodrugs 2006; 20: 3-103.

12. Tanaka T, Tsutsui H, Yoshimoto T, et al. Interleukin 18 is elevated in the sera from patients with atopic dermatitis and from atopic dermatitis model mice, NC/Nga. Int Arch Allergy Immunol 2001; 125: 236-40.

13. Aral M, Arican O, Gul M, et al. The relationship between serum levels of total IgE, IL-18, IL-12, INFgamma and disease severity in children with atopic dermatitis. Mediators Inflamm 2006; 4: 730-98.

14. Yoshimoto T, Mizutani H, Tsutsui H, et al. IL-18 induction of IgE: dependence on CD 4+ T cells, IL-4 and STAT6. Nat Immunol 2000; 1: 132-7.

15. Hoshino T, Wiltrout RH, Young HA. IL-18 is a potent coinducer of Il-13 in Nk and T cell: a new potential role for IL-18 in modulating the immune response. J Immunol 1999; 162: 5070-7.

16. Konishi H, Tsutsui H, Murkami T, et al. IL-18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions. PNAS 2002; 17: 11340-5.

17. Shaker O, El-Komy M, Zeidan N. Possible role of nerve growth factor and IL-18 in pathogenesis of eczematous lesions of atopic dermatitis. J Dermatol Sci 2009; 53: 153-4.

18. Ando M, Shima M. Serum interleukins 12 and 18 and immunoglobulin E concentration and allergic symptoms in Japanese schoolchildren. J Invest Allergol Clin Immunol 2007; 17: 14-9.

19. Xu D, Trajkovic V, Hunter D, et al. IL-18 induces the differentation of Th1 or Th2 cells depending upon cytokine milieu and genetic background. Eur J Immunol 2000; 30: 3147-56.

20. Takubo T, Okura H, Kumara T, et al. Human IL-18 bioactivity in hematological malignancies with highly elevated serum IL-18 levels. Acta Haematol 2000; 103: 162-4.

21. Losy J, Niezgoda A. IL-18 in patients with multiple sclerosis. Acta Neurol Scand 2001; 104: 171-3.

22. Pizarro TT, Michie MH, Bentz M, et al. IL-18, a novel regulatory cytokine, is up-regulated in Crohn’s diseases; expression and localization in intestinal mucosal cells. J Immunol 1999; 162: 6829-35.

23. Nakamura H, Komatsu K, Ayaki M, et al. Serum levels of soluble IL-2 receptor, IL-12, IL-18, and IFN-gamma in patients with acute graft-versus-host disease after allogeneic bone marrow transplantation. J Allergy Clin Immunol 2000; 106: 45-50.

24. Wang D, Drenker M, Eiz-Vesper B, et al. Evidence of pathogenetic role of interleukin 18 in cutaneous lupus erythematosus. Arthritis Rheum 2008; 58: 3205-15.

25. Tsutsui H, Matsui K, Okamura H, et al. Pathophysiological roles of IL-18 in inflammatory liver diseases. Immunol Rev 2000; 174: 192-209.

26. Fassbender K, Mielke O, Bertsch T, et al. Interferon gamma inducing factor IL-18 and interferon gamma in inflammatory CNS diseases. Neurology 1999; 53: 1104-6.

27. Grobmyer SR, Lin E, Lowry SF, et al. Elevation of IL-18 in human sepsis. J Clin Immunol 2000; 20: 212-5.

28. Dzierżanowska-Fangrat K, Michalkiewicz J, Cielecka-Kuszyk J, et al. Enhanced gastric IL-18 mRNA expression in Helicobacter pylori-infected children is associated with macrophage infiltration, IL-8 and IL1beta mRNA expression. Eur J Gastrol Hepatol 2008; 20: 314-9.

29. Sugawara I. Interleukine 18 and infectious diseases with special emphasis on diseases induced by intracellular pathogens. Microbes Infect 2000; 2: 1257-63.

30. Ida A, Tsuji Y, Muranaka J, et al. IL-18 in pregnancy, the elevation of IL-18 in maternal peripheral blood during labour and complicated pregnancies. J Reprod Immunol 2000; 47: 65-74.

31. El-Mezzein REH, Matsumoto T, Nomiyama H, et al. Increased secretion of IL-18 in vitro by peripheral blood mononuclear cells of patients with bronchial asthma and atopic dermatitis. Clin Exp Immunol 2001; 126: 193-8.

32. Wong CK, Ho CY, Ko FWS, et al. Proinflammatory cytokines (IL-17, IL-6, IL-18 and IL-12) and Th cytokines (IFN-gamma, IL-4, IL-10 and IL-13) in patients with allergic asthma. Clin Exp Immunol 2001; 125: 177-83.

33. Tanaka H, Miyazaki N, Oashi K, et al. IL-18 might reflect disease activity in mild and moderate asthma exacerbation. J Allergy Clin Immunol 2001; 107: 331-6.

34. Sebelova S, Izakovicova-Hola L, Stejskalova A, et al. Interleukin 18 and its three polymorphisms relating to allergic rhinitis. J Hum Genet 2007; 52: 152-8.

35. Hon KLE, Leung TF, Ma KC, et al. Serum concentration of IL-18 correlates with disease extent in young children with atopic dermatitis. Pediatr Dermatol 2004; 21: 619-22.

36. Yoshizawa Y, Nomauguchi H, Izaki S, et al. Serum cytokine levels in atopic dermatitis. Exp Dermatol 2002; 27: 225-9.

37. Park S, Youn YH. Clinical significance of serum interleukin 18 concentration in the patient with atopic dermatitis. Korean J Lab Med 2007; 27: 128-32.

38. Lee CC, Lin WY, Wan L, et al. Association of interleukin 18 gene polymorphism with asthma in Chinese patients. J Clin Lab Anal 2008; 22: 39-44.

39. Zhu G, Whyte MK, Vestbo J, et al. Interleukin 18 receptor 1 gene polymorphisms are associated with asthma. Eur J Hum Genet 2008; 16: 1083-90.

40. Reijmerink N, Postma SD, Bruinenberg M, et al. Association of IL1RL1, IL18R1, and IL18RAP gene cluster polymorphisms with asthma and atopy. J Allergy Clin Immunol 2008; 3: 651-3.

41. Trzeciak M, Gleń J, Roszkiewicz J, et al. Association of single nucleotide polymorphism of interleukin-18 with atopic dermatitis. J Eur Acad Dermatol Venereol 2010; 24: 78-9.

42. Robertson MJ, Kirkwood JM, Logan TF, et al. A dose-escalation study of recombinant human interleukin-18 using two different schedules of administration in patients with cancer. Clin Cancer Res 2008; 14: 3462-9.
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