Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.
Immunity. 2011 May 27;34(5):741-54. doi: 10.1016/j.immuni.2011.02.021. Epub 2011 May 19.
Transforming growth factor-β (TGF-β) has been shown to be required for Th17 cell differentiation via Smad-independent mechanisms. The molecular mechanism underlying this pathway remains to be clarified, however. We searched for genes regulated by TGF-β through the Smad-independent pathway by using Smad2 and Smad3 double-deficient T cells and identified the transcription factor Eomesodermin (Eomes), whose expression was suppressed by TGF-β via the c-Jun N-terminal kinase (JNK)-c-Jun signaling pathway. Inhibition of JNK strongly suppressed disease in an in vivo EAE model as well as in vitro Th17 cell induction. Overexpression of Eomes substantially suppressed Th17 cell differentiation, whereas ablation of Eomes expression could substitute for TGF-β in Th17 cell induction in primary T cells. Eomes suppressed Rorc and Il17a promoters by directly binding to the proximal region of these promoters. In conclusion, the suppression of Eomes by TGF-β via the JNK pathway is an important mechanism for Smad-independent Th17 cell differentiation.
转化生长因子-β（TGF-β）已被证明通过 Smad 非依赖性机制对 Th17 细胞分化是必需的。然而，这一途径的分子机制仍有待阐明。我们通过使用 Smad2 和 Smad3 双重缺陷 T 细胞来寻找 TGF-β 通过 Smad 非依赖性途径调节的基因，并鉴定了转录因子 Eomesodermin（Eomes），其表达通过 c-Jun N 末端激酶（JNK）-c-Jun 信号通路被 TGF-β抑制。在体内 EAE 模型和体外 Th17 细胞诱导中，JNK 的抑制强烈抑制疾病。Eomes 的过表达显著抑制 Th17 细胞分化，而 Eomes 表达的缺失可替代 TGF-β在原代 T 细胞中诱导 Th17 细胞。Eomes 通过直接结合这些启动子的近端区域来抑制 Rorc 和 Il17a 启动子。总之，TGF-β 通过 JNK 途径抑制 Eomes 是 Smad 非依赖性 Th17 细胞分化的重要机制。
