Mesenchymal stem cells inhibit Th17 cells differentiation via IFN-γ-mediated SOCS3 activation
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- 作者：Xingxia Liu ; Shaoda Ren ; Xuebin Qu ; Chaozhuo Ge ; Kai Cheng…
- 关键词：MSC ; Th17 ; IFN ; γ ; SOCS3
- 刊名：Immunologic Research
- 出版年：2015
- 出版时间：March 2015
- 年：2015
- 卷：61
- 期：3
- 页码：219-229
- 全文大小：3,428 KB
- 参考文献：1. Bedoui S, Kupz A, Wijburg OL, Walduck AK, Rescigno M, Strugnell RA. Different bacterial pathogens, different strategies, yet the aim is the same: evasion of intestinal dendritic cell recognition. J Immunol. 2010;184(5):2237-2. CrossRef
2. 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-. CrossRef
3. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17?+?T helper cells. Cell. 2006;126(6):1121-3. CrossRef
4. 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;201(2):233-0. CrossRef
5. Amadi-Obi A, Yu CR, Liu X, Mahdi RM, Clarke GL, Nussenblatt RB, et al. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat Med. 2007;13(6):711-. CrossRef
6. Yoshimura T, Sonoda KH, Miyazaki Y, Iwakura Y, Ishibashi T, Yoshimura A, et al. Differential roles for IFN-gamma and IL-17 in experimental autoimmune uveoretinitis. Int Immunol. 2008;20(2):209-4. CrossRef
7. Prod’homme T, Weber MS, Zamvil SS. T effectors outfox T regulators in autoimmunity. Nat Med. 2007;13(4):411-. CrossRef
8. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006;24(2):179-9. CrossRef
9. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235-. doi:10.1038/nature04753 . CrossRef
10. Yoshimura T, Sonoda KH, Ohguro N, Ohsugi Y, Ishibashi T, Cua DJ, et al. Involvement of Th17 cells and the effect of anti-IL-6 therapy in autoimmune uveitis. Rheumatology (Oxford). 2009;48(4):347-4. CrossRef
11. Okuda Y, Sakoda S, Bernard CC, Fujimura H, Saeki Y, Kishimoto T, et al. IL-6-deficient mice are resistant to the induction of experimental autoimmune encephalomyelitis provoked by myelin oligodendrocyte glycoprotein. Int Immunol. 1998;10(5):703-. CrossRef
12. Samoilova EB, Horton JL, Hilliard B, Liu TS, Chen Y. IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells. J Immunol. 1998;161(12):6480-.
13. Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science. 2007;317(5835):256-0. CrossRef
14. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99(10):3838-3. CrossRef
15. Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood. 2003;101(9):3722-.
文摘
Mesenchymal stem cells (MSCs) are immunoregulatory, and the administration of them has been shown to ameliorate inflammation caused by Th17 cells. However, the mechanisms that contribute to MSC regulation on Th17 cell development are unclear. Here, we found that MSCs could inhibit Th17 cell differentiation through the activation of suppressors of cytokine signaling 3 (SOCS3) when coculture of MSCs and CD4+CD25lowCD44lowCD62Lhigh T cells. Further analysis demonstrated that the inhibitory action was mediated via interferon gamma (IFN-γ), which activated signal transducer and activator of transcription-1 (STAT1) to enhance the expression of SOCS3, leading to STAT3 inhibition. Moreover, stable and reciprocal changes in H3K4me3 and H3K27me3 at the promoters of STAT1, STAT3 and RORγt determined the fate of Th17 cells. These results demonstrate that MSCs may inhibit Th17 differentiation via IFN-γ that activates SOCS3 leading to immunomodulatory effects, suggesting a possible mechanism by which MSCs could act as a cellular approach to attenuate the clinical and pathological manifestations of some autoimmune diseases.