Orphan nuclear receptor NR4A2 expressed in T cells from multiple sclerosis mediates production of inflammatory cytokines
Orphan nuclear receptor NR4A2 expressed in T cells from multiple sclerosis mediates production of inflammatory cytokines
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DOI：
10.1073/pnas.0803454105
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发表时间：
2008-06-17
影响因子：
11.1
通讯作者：
Yamamura, Takashi
中科院分区：
文献类型：
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作者：
Doi, Yoshimitsu;Oki, Shinji;Yamamura, Takashi
多发性硬化症 (MS) 是一种由 Th17 和 Th1 细胞介导的中枢神经系统 (CNS) 自身免疫性疾病。 DNA微阵列分析先前表明，孤儿核受体NR4A2在MS的外周血T细胞中强烈上调。在此，我们报告 NR4A2 在介导致病性 T 细胞产生细胞因子方面发挥着关键作用。在实验性自身免疫性脑脊髓炎 (EAE) 中，MS 动物模型 NR4A2 在从中枢神经系统分离的 T 细胞中选择性上调。引人注目的是，NR4A2 的强制表达增强了 IL-17 和 IFN-γ 基因的启动子活性，导致这些细胞因子的过量产生。相反，用 NR4A2 的 siRNA 治疗导致 IL-17 和 IFN-γ 的产生显着减少。此外，NR4A2 siRNA 治疗降低了致脑炎 T 细胞在受体小鼠中转移 EAE 的能力。因此，NR4A2 是触发 MS/EAE 炎症级联的重要转录因子，可作为治疗靶点。
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) mediated by Th17 and Th1 cells. DNA microarray analysis previously showed that NR4A2, an orphan nuclear receptor, is strongly up-regulated in the peripheral blood T cells of MS. Here, we report that NR4A2 plays a pivotal role for mediating cytokine production from pathogenic T cells. In experimental autoimmune encephalomyelitis (EAE), an animal model of MS, NR4A2, was selectively up-regulated in the T cells isolated from the CNS. Strikingly, a forced expression of NR4A2 augmented promoter activities of IL-17 and IFN-gamma genes, leading to an excessive production of these cytokines. Conversely, treatment with siRNA for NR4A2, resulted in a significant reduction in the production of IL-17 and IFN-gamma. Furthermore, treatment with NR4A2 siRNA reduced the ability of encephalitogenic T cells to transfer EAE in recipient mice. Thus, NR4A2 is an essential transcription factor for triggering the inflammatory cascade of MS/EAE and may serve as a therapeutic target.