Cytokine Gene Expression in Newly Diagnosed Multiple Sclerosis Patients
Abstract
Multiple Sclerosis (MS) is characterized by multiple areas of inflammation, demyelination and neurodegeneration. Infiltrating Th1 CD4+ T cells secrete proinflammatory cytokines. They stimulate the release of some cytokines, expression of adhesion molecules and these cytokines may cause damage to the myelin sheath and axons. In this study, we analyzed plasma levels and gene expressions of five important cytokines in the new diagnosed MS Patients by ELISA and Real time PCR. PCR amplifications were performed to determine the IL-17, IL-23, IL-10, IL-27 and TGF-β mRNA expression levels using the SYBR Green PCR Kit. Our results showed significant decrease in IL-10, IL-27 and TGF-β but there was no significant difference in the IL-17 and IL-23 between patients and healthy controls. Altogether, our results indicated that dysregulation of cytokines, mainly increased expression of pro-inflammatory cytokines and decreased expression of inhibitory cytokines occurred in MS patients. This study may shed light to the probable role of these cytokines in neurodegeneration mechanism and current or future use of cytokines in managing and treatment of multiple sclerosis.
1. Compston A, Coles A. Multiple sclerosis. Lancet 2008;372(9648):1502-17.
2. Etemadifar M, Sajjadi S, Nasr Z, Firoozeei TS, Abtahi SH, Akbari M, et al. Epidemiology of multiple sclerosis in Iran: a systematic review. Eur Neurol 2013; 70(5-6):356-63.
3. Tiwari JL, Hodge SE, Terasaki PI, Spence MA. HLA and the inheritance of multiple sclerosis: linkage analysis of 72 pedigrees. Am J Hum Genet 1980; 32(1):103-11.
4. Barcellos LF, Kamdar BB, Ramsay PP, DeLoa C, Lincoln RR, Caillier S, et al. Clustering of autoimmune diseases in families with a high-risk for multiple sclerosis: a descriptive study. Lancet Neurol 2006;5(11):924-31.
5. Nakahara J, Maeda M, Aiso S, Suzuki N. Current concepts in multiple sclerosis: autoimmunity versus oligodendrogliopathy. Clin Rev Allergy Immunol 2012;42(1):26-34.
6. Kebir H, Ifergan I, Alvarez JI, Bernard M, Poirier J, Arbour N, et al. Preferential recruitment of interferon- gamma-expressing TH17 cells in multiple sclerosis. Ann Neurol 2009; 66(3):390-402.
7. Kunz M, Ibrahim SM. Cytokines and cytokine profiles in human autoimmune diseases and animal models of autoimmunity. Mediators Inflamm 2009; 2009:979258.
8. Gyulveszi G, Haak S, Becher B. IL-23-driven encephalo- tropism and Th17 polarization during CNS-inflammation in vivo. Eur J Immunol 2009; 39(7):1864-9.
9. Brucklacher-Waldert V, Stuerner K, Kolster M, Wolthausen J, Tolosa E. Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis. Brain 2009; 132(Pt 12):3329-41.
10. Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B, et al. Phenotypic and functional features of human Th17 cells. J Exp Med 2007;204(8):1849-61.
11. Kroenke MA, Carlson TJ, Andjelkovic AV, Segal BM.IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J Exp Med 2008;205(7):1535-41.
12. Lovett-Racke AE, Yang Y, Racke MK. Th1 versus Th17: are T cell cytokines relevant in multiple sclerosis? Biochim Biophys Acta 2011; 1812(2):246-51.
13. Pette M, Fujita K, Kitze B, Whitaker JN, Albert E, Kappos L, et al. Myelin basic protein-specific T lymphocyte lines from MS patients and healthy individuals. Neurology 1990; 40(11):1770-6.
14. Genain CP, Lee-Parritz D, Nguyen MH, Massacesi L, Joshi N, Ferrante R, et al. In healthy primates, circulating autoreactive T cells mediate autoimmune disease. J Clin Invest 1994; 94(3):1339-45.
15. Imam SA, Guyton MK, Haque A, Vandenbark A, Tyor WR, Ray SK, et al. Increased calpain correlates with Th1 cytokine profile in PBMCs from MS patients. J Neuroimmunol 2007; 190(1-2):139-45.
16. Simpson S, Jr., Stewart N, van der Mei I, Otahal P, Charlesworth J, Ponsonby AL, et al. Stimulated PBMC- produced IFN-gamma and TNF-alpha are associated with altered relapse risk in multiple sclerosis: results from a prospective cohort study. J Neurol Neurosurg Psychiatry 2014.
17. Panitch HS, Hirsch RL, Schindler J, Johnson KP.Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology 1987; 37(7):1097-102.
18. Neukirch F, Lyon-Caen O, Clanet M, Bousquet J, Feingold J, Druet P. Asthma, nasal allergies, and multiple sclerosis. J Allergy Clin Immunol 1997; 99(2):270-1.
19. Gran B, Zhang GX, Yu S, Li J, Chen XH, Ventura ES, et al. IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. J Immunol 2002; 169(12):7104-10.
20. Zhang GX, Gran B, Yu S, Li J, Siglienti I, Chen X, et al.Induction of experimental autoimmune encephalomyelitis in IL-12 receptor-beta 2-deficient mice: IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the central nervous system. J Immunol 2003; 170(4):2153-60.
21. Ferber IA, Brocke S, Taylor-Edwards C, Ridgway W, Dinisco C, Steinman L, et al. Mice with a disrupted IFN- gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunol 1996; 156(1):5-7.
22. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003; 421(6924):744-8.
23. Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 2003; 278(3):1910-4.
24. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005 Jan 17;201(2):233-40.
25. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005; 6(11):1133-41.
26. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005;6(11):1123-32.
27. Hedegaard CJ, Krakauer M, Bendtzen K, Lund H, Sellebjerg F, Nielsen CH. T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis. Immunology 2008 ;125(2):161-9.
28. Haas J, Hug A, Viehover A, Fritzsching B, Falk CS, Filser A, et al. Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. Eur J Immunol 2005;35(11):3343-52.
29. Chen Z, O'Shea JJ. Th17 cells: a new fate for differentiating helper T cells. Immunol Res 2008;41(2):87-102.
30. Tolouei S, Ghaedi K, Khamesipour A, Akbari M, Baghaei M, Hasheminia S, et al. IL-23 and IL-27 Levels in Macrophages Collected from Peripheral Blood of Patients with Healing Vs Non-Healing Form of Cutaneous Leishmaniasis. Iran J Parasitol 2012; 7(1):18-25.
31. Jager A, Dardalhon V, Sobel RA, Bettelli E, Kuchroo VK. Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol 2009;183(11):7169-77.
32. Mueller AM, Pedre X, Killian S, David M, Steinbrecher A. The Decoy Receptor 3 (DcR3, TNFRSF6B) suppresses Th17 immune responses and is abundant in human cerebrospinal fluid. J Neuroimmunol 2009; 209(1-2):57-64.
33. Krakauer M, Sorensen P, Khademi M, Olsson T, Sellebjerg F. Increased IL-10 mRNA and IL-23 mRNA expression in multiple sclerosis: interferon-beta treatment increases IL-10 mRNA expression while reducing IL-23 mRNA expression. Mult Scler 2008; 14(5):622-30.
34. Ramgolam VS, Sha Y, Jin J, Zhang X, Markovic-Plese S.IFN-beta inhibits human Th17 cell differentiation. J Immunol 2009; 183(8):5418-27.
35. Sweeney CM, Lonergan R, Basdeo SA, Kinsella K,Dungan LS, Higgins SC, et al. IL-27 mediates the response to IFN-beta therapy in multiple sclerosis patients by inhibiting Th17 cells. Brain Behav Immun 2011;25(6):1170-81.
36. Axtell RC, Raman C, Steinman L. Interferon-beta exacerbates Th17-mediated inflammatory disease. Trends Immunol 2011; 32(6):272-7.
37. Amedei A, Prisco D, D'Elios MM. Multiple sclerosis: the role of cytokines in pathogenesis and in therapies. Int J Mol Sci 2012; 13(10):13438-60.
38. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69(2):292-302.
39. Matusevicius D, Kivisakk P, He B, Kostulas N, Ozenci V, Fredrikson S, et al. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler 1999; 5(2):101-4.
40. Babaloo Z, Yeganeh RK, Farhoodi M, Baradaran B, Bonyadi M, Aghebati L. Increased IL-17A but decreased IL-27 serum levels in patients with multiple sclerosis. Iran J Immunol 2013; 10(1):47-54.
41. Kallaur AP, Oliveira SR, Colado Simao AN, Delicato de Almeida ER, Kaminami Morimoto H, Lopes J, et al. Cytokine profile in relapsingremitting multiple sclerosis patients and the association between progression and activity of the disease. Mol Med Rep 2013; 7(3):1010-20.
42. Romagnani S. Regulation of the T cell response. Clin ExpAllergy 2006; 36(11):1357-66.
43. Vaknin-Dembinsky A, Balashov K, Weiner HL. IL-23 is increased in dendritic cells in multiple sclerosis and down-regulation of IL-23 by antisense oligos increases dendritic cell IL-10 production. J Immunol 2006;176(12):7768-74.
44. Carrieri PB, Provitera V, De Rosa T, Tartaglia G, Gorga F, Perrella O. Profile of cerebrospinal fluid and serum cytokines in patients with relapsing-remitting multiple sclerosis: a correlation with clinical activity. Immunopharmacol Immunotoxicol 1998; 20(3):373-82.
45. Calabresi PA, Tranquill LR, McFarland HF, Cowan EP.Cytokine gene expression in cells derived from CSF of multiple sclerosis patients. J Neuroimmunol 1998; 89(1-2):198-205.
46. Cucci A, Barbero P, Clerico M, Ferrero B, Versino E, Contessa G, et al. Pro-inflammatory cytokine and chemokine mRNA blood level in multiple sclerosis is related to treatment response and interferon-beta dose. J Neuroimmunol 2010; 226(1-2):150-7.
47. Meyer AL, Benson J, Song F, Javed N, Gienapp IE, Goverman J, et al. Rapid depletion of peripheral antigen- specific T cells in TCR-transgenic mice after oral administration of myelin basic protein. J Immunol 2001;166(9):5773-81.
48. Racke MK, Cannella B, Albert P, Sporn M, Raine CS, McFarlin DE. Evidence of endogenous regulatory function of transforming growth factor-beta 1 in experimental allergic encephalomyelitis. Int Immunol 1992; 4(5):615-20.
49. Su LF. Updates on high-throughput molecular profiling for the study of rheumatoid arthritis. Isr Med Assoc J 2008; 10(4):307-9.
50. Pot C, Jin H, Awasthi A, Liu SM, Lai CY, Madan R, et al. Cutting edge: IL-27 induces the transcription factor c- Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J Immunol 2009; 183(2):797-801.
51. Fitzgerald DC, Ciric B, Touil T, Harle H, Grammatikopolou J, Das Sarma J, et al. Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis. J Immunol 2007; 179(5):3268-75.
52. Wynick C, Petes C, Gee K. Interleukin-27 Mediates Inflammation During Chronic Disease. J Interferon Cytokine Res 2014.
53. Vogelgesang A, Rosenberg S, Skrzipek S, Broker BM, Dressel A. Mitoxantrone treatment in multiple sclerosis induces TH2-type cytokines. Acta Neurol Scand 2010;122(4):237-43.
54. Hong J, Li N, Zhang X, Zheng B, Zhang JZ. Induction of CD4+CD25+ regulatory T cells by copolymer-I through activation of transcription factor Foxp3. Proc Natl Acad Sci U S A 2005; 102(18):6449-54.
Files | ||
Issue | Vol 14, No 2 (2015) | |
Section | Articles | |
Keywords | ||
Autoimmunity Cytokines Inflammation Multiple Sclerosis Neurodegeneration |
Rights and permissions | |
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |