Iranian Journal of Allergy, Asthma and Immunology 2017. 16(4):329-337.

Correlation of Serum Levels of IL-33, IL-37, Soluble Form of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), and Circulatory Frequency of VEGFR2-expressing Cells with Multiple Sclerosis Severity
Ebrahim Kouchaki, Omid Reza Tamtaji, Ehsan Dadgostar, Mohammad Karami, Hassan Nikoueinejad, Hossein Akbari


IL-33 and IL-37 (new cytokines of IL-1 family), soluble form of vascular endothelial growth factor receptor-2 (sVEGFR2) as well as membranous expression of VEGFR2 have some key roles in the pathogenesis of autoimmune and inflammatory diseases. The aim of this study was to correlate circulatory changes of these factors with the severity of multiple sclerosis (MS) as an autoimmune and inflammatory disease. Our case-control study was performed on 84 patients with MS and 75 healthy subjects. The serum levels of IL-33, IL-37 and sVEGFR2 in the peripheral blood samples of all participants were measured by enzyme-linked immune sorbent assay (ELISA). Flow cytometry was used to analyze the circulatory number of VEGFR2-expressing cells. The severity of MS was evaluated using the expanded disability status scale (EDSS). Finally, we evaluated the correlation between serum levels of those factors with disease severity. Our findings showed that the serum level of IL-33, IL-37, sVEGFR2 and the circulatory number of VEGFR2-expressing cells were increased in patients with MS compared to healthy subjects (p<0.0001). Also, there was a significant correlation between serum levels of these 3 factors with disease severity according to EDSS. Our study showed that the serum levels of IL-33, IL-37 and sVEGFR2 may be important prognostic biomarkers of MS.


Interleukin-33, Interleukin-37; Multiple sclerosis; Soluble vascular endothelial growth factor 2; Vascular endothelial growth factor 2-expressing cells

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1. Goldenberg MM. Multiple sclerosis review. P T 2012; 37(3):175-84.

2. Murray TJ. Diagnosis and treatment of multiple sclerosis. BMJ 2006; 332(7540):525-7.

3. Etemadifar M, Maghzi A-H. Sharp increase in the incidence and prevalence of multiple sclerosis in Isfahan, Iran. Mult Scler 2011; 17(8):1022-7.

4. Moghtaderi A, Rakhshanizadeh F, Shahraki-Ibrahimi S. Incidence and prevalence of multiple sclerosis in southeastern Iran. Clin Neurol Neurosurg 2013; 115.

5. Balashov KE, Smith DR, Khoury SJ, Hafler DA, Weiner HL. Increased interleukin 12 production in progressive multiple sclerosis: induction by activated CD4+ T cells via CD40 ligand. J Proc Natl Acad Sci U S A 1997; 94(2):599-603.

6. Nicoletti F, Di Marco R, Mangano K, Patti F, Reggio E, Nicoletti A, et al. Increased serum levels of interleukin-18 in patients with multiple sclerosis. Neurology 2001; 57(2):342-4.

7. Mikova O, Yakimova R, Bosmans E, Kenis G, Maes M. Increased serum tumor necrosis factor alpha concentrations in major depression and multiple sclerosis. Eur Neuropsychopharmacol 2001; 11(3):203-8.

8. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. 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 2005; 23(5):479-90.

9. Kakkar R, Hei H, Dobner S, Lee RT. Interleukin 33 as a mechanically responsive cytokine secreted by living cells. J Biol Chem 2012; 287(9):6941–8.

10. Mirchandani AS, Salmond RJ, Liew FY. Interleukin-33 and the function of innate lymphoid cells. Trends Immunol 2012; 33(8):389–96

11. Christophi GP, Gruber RC, Panos M, Christophi RL, Jubelt B, Massa PT. Interleukin-33 upregulation in peripheral leukocytes and CNS of multiple sclerosis patients. Clin Immunol 2012; 142(3):308-19.

12. Suttle MM, Nilsson G, Snellman E, Harvima I. Experimentally induced psoriatic lesion associates with interleukin (IL)‐6 in mast cells and appearance of dermal cells expressing IL‐33 and IL‐6 receptor. Clin Exp Immunol 2012; 169(3):311-9.

13. Talabot-Ayer D, McKee T, Gindre P, Bas S, Baeten DL, Gabay C, et al. Distinct serum and synovial fluid interleukin (IL)-33 levels in rheumatoid arthritis, psoriatic arthritis and osteoarthritis. J Joint Bone Spine 2012; 79(1):32-7.

14. Christophi GP, Gruber RC, Panos M, Christophi RL, Jubelt B, Massa PT. Interleukin-33 upregulation in peripheral leukocytes and CNS of multiple sclerosis patients. Clin Immunol 2012; 142(3):308-19.

15. Zhang F, Tossberg JT, Spurlock CF, Yao SY, Aune TM, Sriram S. Expression of IL‐33 and its epigenetic regulation in multiple sclerosis. Ann Clin Transl Neurol 2014; 1(5):307-18.

16. Sharma S, Kulk N, Nold MF, Gräf R, Kim S-H, Reinhardt D, et al. The IL-1 family member 7b translocates to the nucleus and down-regulates proinflammatory cytokines. J Immunol 2008; 180(8):5477-82.

17. Bufler P, Gamboni-Robertson F, Azam T, Kim SH, Dinarello CA. Interleukin-1 homologues IL-1F7b and IL-18 contain functional mRNA instability elements within the coding region. responsive to lipopolysaccharide. Biochem J 2004; 381(pt2):503-10.

18. Li Y, Wang Z, Yu T, Chen B, Zhang J, Huang K, et al. Increased expression of IL-37 in patients with Graves' disease and its contribution to suppression of proinflammatory cytokines production in peripheral blood mononuclear cells. PLoS One 2014; 9(9):e107183.

19. Liu W, Deng L, Chen Y, Sun C, Wang J, Zhou L, et al. Anti-Inflammatory Effect of IL-37b in Children with Allergic Rhinitis. Mediators Inflamm 2014; 2014:746846.

20. Ji Q, Zeng Q, Huang Y, Shi Y, Lin Y, Lu Z, et al. Elevated plasma IL-37, IL-18, and IL-18BP concentrations in patients with acute coronary syndrome. Mediators Inflamm 2014; 2014, 165742.

21. Farrokhi M, Rezaei A, Amani-Beni A, Etemadifar M, Kouchaki E, Zahedi A. Increased serum level of IL-37 in patients with multiple sclerosis and neuromyelitis optica. Acta Neurol Belg 2015; 115(4):609-14.

22. Plate KH. Mechanisms of angiogenesis in the brain. J Neuropathol Exp Neurol 1999; 58(4): 313-20.

23. Folkman J, Shing Y. Angiogenesis. J Biol Chem 1992; 267(16):10931-4.

24. Creamer D, Sullivan D, Bicknell R, Barker J. J Angiogenesis in psoriasis. Angiogenesis 2002; 5(4):231-6.

25. Kirk SL, Karlik SJ. VEGF and vascular changes in chronic neuroinflammation. J Autoimmun 2003; 21(4):353-63.

26. Robinson CJ, Stringer SE. The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci 2001; 114(Pt 5):853-65.

27. Kasap M, Sazci A. The comparison of VEGFR-1-binding domain of VEGF-A with modelled VEGF-C sheds light on receptor specificity. J Theor Biol 2008; 253(3):446-51.

28. Ebos JM, Bocci G, Man S, Thorpe PE, Hicklin DJ, Zhou D, Jia X, Kerbel RS. A naturally occurring soluble form of vascular endothelial growth factor receptor 2 detected in mouse and human plasma. Mol Cancer Res 2004; 2(6):315-26.

29. Ebos JM, Lee CR, Bogdanovic E, Alami J, Van Slyke P, Francia G, et al. Vascular endothelial growth factor-mediated decrease in plasma soluble vascular endothelial growth factor receptor-2 levels as a surrogate biomarker for tumor growth. Cancer Res 2008; 68(2):521-9.

30. Kouchaki E, Otroshi Shahreza B, Faraji S, Nikoueinejad H, Sehat M. Iran J Allergy Asthma Immunol 2016; 15(3):204-11.

31. Matsuyama Y, Okazaki H, Tamemoto H, Kimura H, Kamata Y, Nagatani K, et al. Increased levels of interleukin 33 in sera and synovial fluid from patients with active rheumatoid arthritis. J Rheumatol 2010; 37(1):18-25.

32. Han GW, Zeng LW, Liang CX, Cheng BL, Yu BS, Li HM, et al. Serum levels of IL-33 is increased in patients with ankylosing spondylitis. Clin Rheumatol 2011; 30(12):1583-8.

33. Hamzaoui K, Kaabachi W, Fazaa B, Zakraoui L, Mili-Boussen I, Haj Sassi F. Serum IL-33 levels and skin mRNA expression in Behcet's disease. Clin Exp Rheumatol 2012; 31(3 Suppl 77):6-14.

34. Jung SM, Lee J, Baek SY, Lee JH, Lee J, Park KS, et al. The Interleukin 33/ST2 Axis in Patients with Primary Sjögren Syndrome: Expression in Serum and Salivary Glands, and the Clinical Association. J Rheumatol 2015; 42(2):264-71.

35. Shen J, Shang Q, Wong CK, Li EK, Wang S, Li RJ, et al. IL-33 and soluble ST2 levels as novel predictors for remission and progression of carotid plaque in early rheumatoid arthritis: A prospective study. Semin Arthritis Rheum 2015; 45(1):18-27.

36. Beltrán CJ, Núñez LE, Díaz‐Jiménez D, Farfan N, Candia E, Heine C, et al. Characterization of the novel ST2/IL‐33 system in patients with inflammatory bowel disease. Inflamm Bowel Dis 2010; 16(7):1097-107.

37. Kearley J, Buckland KF, Mathie SA, Lloyd CM. Resolution of Allergic Inflammation and Airway Hyperreactivity Is Dependent upon Disruption of the T1/ST2–IL-33 Pathway. Am J Respir Crit Care Med 2009; 179(9):772-81.

38. Zarpelon A, Cunha T, Alves‐Filho J, Pinto L, Ferreira S, McInnes I, et al. IL‐33/ST2 signalling contributes to carrageenin‐induced innate inflammation and inflammatory pain: role of cytokines, endothelin‐1 and prostaglandin E2. Br J Pharmacol 2013; 169(1):90-101.

39. Sharief MK, Hentges R. Association between tumor necrosis factor-α and disease progression in patients with multiple sclerosis. N Engl J Med 1991; 325(7):467-72.

40. Padberg F, Feneberg W, Schmidt S, Schwarz M, Körschenhausen D, Greenberg B, et al. CSF and serum levels of soluble interleukin-6 receptors (sIL-6R and sgp130), but not of interleukin-6 are altered in multiple sclerosis. J neuroimmunol 1999; 99(2):218-23.

41. Luomala M, Lehtimäki T, Huhtala H, Ukkonen M, Koivula T, Hurme M, et al. Promoter polymorphism of IL‐10 and severity of multiple sclerosis. Acta Neurol Scand 2003; 108(6):396-400.

42. Nold MF, Nold-Petry CA, Zepp JA, Palmer BE, Bufler P, Dinarello CA. IL-37 is a fundamental inhibitor of innate immunity. Nat Immunol 2010;11(11):1014-22.

43. Chen B, Huang K, Ye L, Li Y, Zhang J, Zhang J, et al. Interleukin-37 is increased in ankylosing spondylitis patients and associated with disease activity. J Transl Med 2015; 13(1):1-9.

44. Xia L, Shen H, Lu J. Elevated serum and synovial fluid levels of interleukin-37 in patients with rheumatoid arthritis: Attenuated the production of inflammatory cytokines. Cytokine 2015; 76(2):553-7.

45. Charrad R, Berraïes A, Hamdi B, Ammar J, Hamzaoui K, Hamzaoui A. Anti-Inflammatory activity of IL-37 in Asthmatic Children: Correlation with Inflammatory Cytokines TNF-α, IL-β, IL-6 and IL-17A. Immunobiology 2015; 221(2):182-7.

46. Xu D, Wang A, Jiang F, Hu J, Zhang X. Effects of interleukin-37 on cardiac function after myocardial infarction in mice. Int J Clin Exp Pathol 2015; 8(5):5247-51.

47. Nold-Petry CA, Lo CY, Rudloff I, Elgass KD, Li S, Gantier MP, et al. IL-37 requires the receptors IL-18R [alpha] and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction. Nat Immunol 2015; 16(4):354-65.

48. Ballara S, Taylor PC, Reusch P, Marme D, Feldmann M, Maini RN, Paleolog EM. Raised serum vascular endothelial growth factor levels are associated with destructive change in inflammatory arthritis. Arthritis Rheum 2001; 44(9):2055-64.

49. Miotla J, Maciewicz R, Kendrew J, Feldmann M, Paleolog E. Treatment with soluble VEGF receptor reduces disease severity in murine collagen-induced arthritis. Lab Invest 2000; 80(8):1195-205.

50. Ahnert P, Kirsten H. Association of ITGAV supports a role of angiogenesis in rheumatoid arthritis. Arthritis Res Ther 2007; 9(5):108.

51. Koch AE, Distler O. Vasculopathy and disordered angiogenesis in selected rheumatic diseases: rheumatoid arthritis and systemic sclerosis. Arthritis Res Ther 2007; 9 Suppl 2:S3.

52. Holmes K, Roberts OL, Thomas AM, Cross MJ. Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal 2007; 19(10):2003-12.


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