Chan Michael W Y, Chang Chia-Bin, Tung Chien-Hsueh, Sun Justin, Suen Jau-Ling, Wu Shu-Fen
Department of Life Science and Institute of Molecular Biology, National Chung-Cheng University, Min-Hsiung, Chia-Yi, Taiwan, Republic of China.
Department of Life Science and Institute of Molecular Biology, National Chung-Cheng University, Min-Hsiung, Chia-Yi, Taiwan, Republic of China Division of Allergy, Immunology and Rheumatology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Dalin, Chia-Yi, Taiwan, Republic of China.
Mol Med. 2014 Jun 26;20(1):248-56. doi: 10.2119/molmed.2013.00159.
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-γ 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.
叉头框蛋白P3（Foxp3）是控制调节性T（Treg）细胞发育和功能的主要转录因子。先前的研究表明Foxp3表达存在表观遗传调控。在此，我们通过使用小鼠实验性自身免疫性脑脊髓炎（EAE）模型，研究外周应用脱氧核糖核酸（DNA）甲基转移酶抑制剂5-氮杂-2'-脱氧胞苷（5-Aza）是否能调节中枢神经系统（CNS）炎症。我们发现，用低剂量（0.15 mg/kg）5-Aza短暂预处理的髓鞘少突胶质细胞糖蛋白（MOG）肽诱导的EAE小鼠的疾病活动受到抑制，促炎细胞因子大幅减少，表明中枢神经系统炎症反应得到显著改善。相反，对照EAE小鼠表达高水平的干扰素-γ（IFN-γ）和白细胞介素（IL）-17。此外，体外5-Aza处理增加了从绿色荧光蛋白（GFP）敲入Foxp3转基因小鼠分离的CD4(+)GFP(-) T细胞中的GFP表达。重要的是，5-Aza处理在疾病发作和高峰期均增加了EAE小鼠中Treg细胞的数量。然而，Treg抑制试验表明，5-Aza处理并未增强单个Treg细胞的抑制功能，但确实维持了EAE小鼠效应细胞较低的激活阈值。总之，5-Aza处理通过增加外周Treg细胞数量和抑制效应细胞，预防了EAE的发展并抑制了中枢神经系统炎症。
