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IL-38 serum levels in patients with Behcet’s disease and the relationship with clinical features

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Behcet’s disease (BD) is a chronic multisystem autoimmune disorder. Various cytokines take part in the pathogenesis of this disease. Interleukin (IL)-38, a new member of IL-1 cytokine family, has been reported to have antiinflammatory properties; however, its role in BD has not been investigated yet. In this study, we aimed to examine the probable role of IL-38 in the clinical context of BD. A total of 81 patients with BD and 81 age- and sex-matched healthy subjects as controls were included in this study. The serum levels of IL-38 were measured in patients and controls sera using enzyme-linked immunosorbent assay. The relationship between the serum levels of IL-38 and clinical and laboratory characteristics of the patients were determined. IL-38 serum levels were significantly lower in patients in comparison with healthy controls at P = 0.003. We found significant differences between IL-38 levels in BD patients with positive and negative pathergy tests (P = 0.048) and patients with and without eye involvement (P = 0.046). Despite the absence of significant differences in serum levels between male and female patients, IL-38 levels were higher in female patients with a positive pathergy test (P = 0.048) and those patients with eye involvement (P = 0.046). As healthy controls showed higher IL-38 serum levels than patients, a protective anti-inflammatory role of IL-38 in BD is suggested. Together, these results suggest that the positive relationship between IL-38 serum levels and eye involvement that IL-38 may play a role in this clinical feature of the disease.

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  1. 1.

    Tong B, Liu X, Xiao J, Su G. Immunopathogenesis of Behcet’s disease Frontiers Immunol 2019; 10: 665.

  2. 2.

    Davcakir N, Dervis E, Benian O, et al. Prevalence of Behcet’s disease in rural western Turkey: a preliminary report. Clin Exp Rheumatol 2004; 22: S53–5.

  3. 3.

    Galeone M, Colucci R, D’Erme AM, Moretti S, Lotti T. Potential infectious etiology of Behçet’s disease. Patholog Res Int 2012; 2012: 595380.

  4. 4.

    Mashall SE. Behcet’s disease. Best Pract Res Clin Rheumatol 2004; 18: 291.

  5. 5.

    Takeuchi M, Kastner DL, Remmers EF. The immunogenetics of Behçet’s disease: a comprehensive review. J Autoimmun 2015; 64: 137.

  6. 6.

    de Chambrun MP, Wechsler B, Geri G, Cacoub P, Saadoun D. Remmers New insights into the pathogenesis of Behcet’s disease. Autoimmunity Rev 2012; 11: 687.

  7. 7.

    Koarada S, Haruta Y, Tada Y, et al. Remmers Increased entry of CD4+ T cells into the Th1 cytokine effector pathway during T-cell division following stimulation in Behcet’s disease. Rheumatology 2004; 43: 843.

  8. 8.

    Ben Ahmed M, Houman H, Miled M, Dellagi K, Louzir H. Remmers Involvement of chemokines and Thl cytokines in the pathogenesis of mucocutaneous lesions of Behcet’s disease. Arthritis Rheumatol 2004; 50: 2291.

  9. 9.

    Gholijani N, Ataollahi MR, Samiei A, Aflaki E, Shenavandeh S, Kamali-Sarvestani E. An elevated pro-inflammatory cytokines profile in Behcet’s disease: a multiplex analysis. Immunol Lett 2017; 186: 46.

  10. 10.

    Nanke Y, Yago T, Kotake S. The role of Thl7 cells in the pathogenesis of Behcet’s disease. J Clin Med 2017; 6: 74.

  11. 11.

    Aktas Cetin E, Cosan F, Cene A, Deniz G Deniz IL-22-secreting Th22 and IFN-γ-secreting Th17 cells in Behçet’s disease. Modern Rheumatol 2014; 24: 802.

  12. 12.

    Shimizu J, Takai K, Fujiwara N, et al. Deniz Excessive CD4+ T cells co-expressing interleukin-17 and interferon-γ in patients with Behçet’s disease. Clin Exp Immunol 2012; 168: 68.

  13. 13.

    Direskeneli H, Fujita H, Akdis CA. Akdis Regulation of TH17 and regulatory T cells in patients with Behcet disease. J Allergy Clin Immunol 2011; 128: 665.

  14. 14.

    Lin H, Ho AS, Haley-Vicente D, et al. Akdis Cloning and characterization of IL-1HY2, a novel interleukin-1 family member. J Biol Chem 2001; 276: 20597.

  15. 15.

    Nicklin MJH, Barton JL, Nguyen M, FitzGerald MG, Duff GW, Kornman K. Akdis A sequence-based map of the nine genes of the human interleukin-1 cluster. Genomics 2002; 79: 718.

  16. 16.

    Bensen JT, Dawson PA, Mychaleckyj JC, Bowden DW. Identification of a novel human cytokine gene in the interleukin gene cluster on chromosome 2ql2-14. J Interferon Cytokine Res 2001; 21: 899.

  17. 17.

    Gabay C, Towne JE. Regulation and function of interleukin-36 cytokines in homeostasis and pathological conditions. J Leuk Biol 2015; 97: 645.

  18. 18.

    Hahn M, Frey S, Hueber AJ. The novel interleukin-1 cytokine family members in inflammatory diseases. Curr Opin Rheumatol 2017; 29: 208.

  19. 19.

    Jung MY, Kang SW, Kim SK, et al. The interleukin-1 family gene polymorphisms in Korean patients with rheumatoid arthritis. Scand J Rheumatol 2010; 39: 190.

  20. 20.

    Rahman P, Sun S, Peddle L, Snelgrove T, Melay W, Greenwood C, et al. Association between the interleukin-1 family gene cluster and psoriatic arthritis. Arthritis Rheumatol 2006; 54: 2321.

  21. 21.

    Guo ZS, Li C, Lin ZM, et al. Association of IL-1 gene complex members with ankylosing spondylitis in Chinese Han population. Int J Immunogenet 2010; 37: 33.

  22. 22.

    Dehghan A, Dupuis J, Barbalic M, et al. Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. Circulation 2011; 123: 731.

  23. 23.

    Wang M, Wang B, Ma Z, et al. Detection of the novel IL-1 family cytokines by QAH-IL1F-1 assay in rheumatoid arthritis. Cell Mol Biol 2016; 62: 31.

  24. 24.

    Rudloff I, Godsell J, Nold-Petry CA, et al. Brief Report: interleukin-38 exerts anti-inflammatory functions and is associated with disease activity in systemic lupus erythematosus. Arthritis Rheumatol 2015; 67: 3219.

  25. 25.

    Wang H-J, Jiang Y-F, Wang X-R, Zhang M-L, Gao P-J. Elevated serum interleukin-38 level at baseline predicts virological response in telbivudine-treated patients with chronic hepatitis B. World J Gastroenterol 2016; 22: 4529.

  26. 26.

    Zhong Y, Yu K, Wang X, Wang X, Ji Q, Zeng Q. Elevated plasma IL-38 concentrations in patients with acute ST-segment elevation myocardial infarction and their dynamics after reperfusion treatment. Mediators Inflamm 2015; 2015: 490120.

  27. 27.

    Chu M, Chu I, Yung E, et al. Aberrant expression of novel cytokine IL-38 and regulatory T lymphocytes in childhood asthma. Molecules 2016; 21: 933.

  28. 28.

    Takenaka S, Kaieda S, Kawayama T, et al. IL-38: a new factor in rheumatoid arthritis. Biochem Biophy Rep 2015; 4: 386.

  29. 29.

    Boutet MA, Bart G, Penhoat M, et al. Distinct expression of interleukin (IL)-36alpha, beta and gamma, their antagonist IL-36Ra and IL-38 in psoriasis, rheumatoid arthritis and Crohn’s disease. Clin Exp Immunol 2016; 184: 159.

  30. 30.

    Yazici H, Yazici Y. Criteria for Behçet’s disease with reflections on all disease criteria. J Autoimmunity 2014; 48: 104.

  31. 31.

    International Team for the Revision of the International Criteria for Behçet’s Disease (ITR-ICBD). The International Criteria for Behçet’s Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. J Eur Acad Dermatol Venereol 2014; 28: 338.

  32. 32.

    van de Veerdonk FL, Stoeckman AK, Wu G, et al. IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist. Proc Natl Acad Sci USA 2012; 109: 3001.

  33. 33.

    Cozzani E, Drosera M, Gasparini GA-O, Parodi A. Serology of lupus erythematosus: correlation between immunopathological features and clinical aspects. Autoimmune Dis 2014; 2014: 321359.

  34. 34.

    Nowatzky J, Chajek-Shaul T. Biomarkers in Behcet’s disease: diagnosis and disease activity. Int J Clin Rheum 2009; 4: 271.

  35. 35.

    Türsen Ü. Pathophysiology of the Behcet’s disease. Pathol Res Int 2012; 2012: 493015.

  36. 36.

    Shimizu J, Yoshikawa H, Takada E, Hirotsu C, Suzuki N. Unbalanced helper T cell function in Behcet’s disease. Inflamm Regen 2011; 31: 296.

  37. 37.

    Hamzaoui K. Th17 cells in Behcet’s disease: a new immunoreg-ulatory axis. Clin Exp Rheumatol 2011; 29: 71.

  38. 38.

    Davatchi F, Chams-Davatchi C, Ghodsi Z, et al. Diagnostic value of pathergy test in Behcet’s disease according to the change of incidence over the time. Clin Rheumatol 2011; 30: 1151.

  39. 39.

    Belguendouz H, Messaoudène D, Lahmar K, et al. Interferon-γ and nitric oxide production during Behçet uveitis: immunomodulatory effect of interleukin-10. J Interferon Cytokine Res 2011; 31: 643.

  40. 40.

    Park UC, Kim TW, Yu HG. Immunopathogenesis of ocular Behçet’s disease. J Immunol Res 2014; 2014: 653539.

  41. 41.

    Yu HG, Lee DS, Seo JM, et al. The number of CD8+ T cells and NKT cells increases in the aqueous humor of patients with Behçet’s uveitis. Clin Exp Immunol 2004; 137: 437.

  42. 42.

    Belguendouz H, Messaoudene D, Hartani D, et al. Effect of corticotherapy on interleukin-8 and -12 and nitric oxide production during Behçet and idiopathic uveitis. J Fr Ophtalmol 2008; 31: 387.

  43. 43.

    Mora J, Schlemmer A, Wittig I, et al. Interleukin-38 is released from apoptotic cells to limit inflammatory macrophage responses. J Mol Cell Biol 2016; 8: 426.

  44. 44.

    Shenavandeh S, Jahanshahi KA, Aflaki E, Tavassoli A. Frequency of HLA-B5, HLA-B51 and HLA-B27 in patients with idiopathic uveitis and Behçet’s disease: a case-control study. Reumatologia 2018; 56: 67.

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Research reported in this publication was supported by Elite Researcher Grant Committee under award number [971223] from the National Institute for Medical Research Development (NIMAD), Tehran, Iran.

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Correspondence to Zahra Amirghofran.

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Conflicts of Interest

The authors declare no conflicts of interest.

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Zarrabi, M., Gholijani, N., Shenavandeh, S. et al. IL-38 serum levels in patients with Behcet’s disease and the relationship with clinical features. Eur Cytokine Netw 30, 82–87 (2019).

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  • IL-38
  • Behcet’s disease
  • autoimmune disease
  • cytokine