Doi Yoshimitsu, Oki Shinji, Ozawa Tomoko, Hohjoh Hirohiko, Miyake Sachiko, Yamamura Takashi
Departments of Immunology and Molecular Genetics, National Institute of Neuroscience, National Center of Neurology and Psychiatry,4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8381-6. doi: 10.1073/pnas.0803454105. Epub 2008 Jun 11.
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.
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微阵列分析先前显示，孤儿核受体NR4A2在MS患者外周血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起关键作用。在MS的动物模型实验性自身免疫性脑脊髓炎（EAE）中，从CNS分离的T细胞中NR4A2被选择性上调。令人惊讶的是，NR4A2的强制表达增强了IL-17和IFN-γ基因的启动子活性，导致这些细胞因子过度产生。相反，用针对NR4A2的siRNA处理导致IL-17和IFN-γ的产生显著减少。此外，用NR4A2 siRNA处理降低了致脑炎性T细胞在受体小鼠中转移EAE的能力。因此，NR4A2是触发MS/EAE炎症级联反应的必需转录因子，可能成为治疗靶点。
