Low-Dose 5-Aza-2′-deoxycytidine Pretreatment Inhibits Experimental Autoimmune Encephalomyelitis by Induction of Regulatory T Cells
Low-Dose 5-Aza-2′-deoxycytidine Pretreatment Inhibits Experimental Autoimmune Encephalomyelitis by Induction of Regulatory T Cells
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DOI：
10.2119/molmed.2013.00159
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发表时间：
2014-01-01
影响因子：
5.7
通讯作者：
Wu, Shu-Fen
中科院分区：
文献类型：
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作者：
Chan, Michael W. Y.;Chang, Chia-Bin;Wu, Shu-Fen
叉头盒P3（Foxp 3）是控制调节性T（Treg）细胞发育和功能的主要转录因子。以前的研究表明Foxp 3表达的表观遗传调控。在这里，我们研究是否脱氧核糖核酸（DNA）甲基转移酶抑制剂5-氮杂-2 '-脱氧胞苷（5-Aza）外周应用可以调节中枢神经系统（CNS）炎症，通过使用小鼠实验性自身免疫性脑脊髓炎（EAE）模型。我们发现，疾病的活动被抑制在髓鞘少突胶质细胞糖蛋白（MOG）肽诱导的EAE小鼠简单地预处理低剂量（0.15毫克/公斤）5-氮杂，改善显着的中枢神经系统炎症反应，大大减少促炎细胞因子。相反，对照EAE小鼠表达高水平的IFN-γ和白细胞介素（IL）-17。此外，5-Aza体外处理增加了从GFP敲入Foxp 3转基因小鼠分离的CD 4（+）GFP（-）T细胞中的GFP表达。重要的是，5-Aza治疗增加了EAE小鼠在疾病发作和高峰时的Treg细胞数量。然而，Treg抑制测定显示5-Aza处理不增强每细胞Treg抑制功能，但确实维持EAE小鼠中效应细胞的较低活化阈值。总之，5-Aza治疗通过增加外周Treg细胞的数量和抑制效应细胞来预防EAE的发展并抑制CNS炎症。
Forkhead box P3 (Foxp3) is the major transcription factor controlling the development and function of regulatory T (Treg) cells. Previous studies have indicated epigenetic regulation of Foxp3 expression. Here, we investigated whether the deoxyribonucleic acid (DNA) methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-Aza) applied peripherally could modulate central nervous system (CNS) inflammation, by using a mouse experimental autoimmune encephalomyelitis (EAE) model. We found that disease activity was inhibited in a myelin oligodendrocyte glycoprotein (MOG) peptide-induced EAE mouse briefly pretreated with low-dose (0.15 mg/kg) 5-Aza, ameliorating significant CNS inflammatory responses, as indicated by greatly decreased proinflammatory cytokines. On the contrary, control EAE mice expressed high levels of IFN-gamma and interleukin (IL)-17. In addition, 5-Aza treatment in vitro increased GFP expression in CD4(+) GFP(-) T cells isolated from GFP knock-in Foxp3 transgenic mice. Importantly, 5-Aza treatment increased Treg cell numbers, in EAE mice, at both disease onset and peak. However, Treg inhibition assays showed 5-Aza treatment did not enhance per-cell Treg inhibitory function, but did maintain a lower activation threshold for effector cells in EAE mice. In conclusion, 5-Aza treatment prevented EAE development and suppressed CNS inflammation, by increasing the number of Treg cells and inhibiting effector cells in the periphery.