Department for Pharmacology and Genetics, Medical University Innsbruck, Peter Mayr Str. 1a, A-6020 Innsbruck, Austria.
J Autoimmun. 2012 Dec;39(4):428-40. doi: 10.1016/j.jaut.2012.07.007. Epub 2012 Aug 24.
Interleukin-17A (IL-17A) is the signature cytokine produced by Th17 CD4(+) T cells and has been tightly linked to autoimmune pathogenesis. In particular, the transcription factors NFAT and RORγt are known to activate Il17a transcription, although the detailed mechanism of action remains incompletely understood. Here, we show that the nuclear orphan receptor NR2F6 can attenuate the capacity of NFAT to bind to critical regions of the Il17a gene promoter. In addition, because NR2F6 binds to defined hormone response elements (HREs) within the Il17a locus, it interferes with the ability of RORγt to access the DNA. Consistently, NFAT and RORγt binding within the Il17a locus were enhanced in Nr2f6-deficient CD4(+) Th17 cells but decreased in Nr2f6-overexpressing transgenic CD4(+) Th17 cells. Taken together, our findings uncover an example of antagonistic regulation of Il17a transcription through the direct reciprocal actions of NR2F6 versus NFAT and RORγt.
白细胞介素-17A (IL-17A) 是 Th17 CD4(+) T 细胞产生的特征性细胞因子，与自身免疫发病机制密切相关。特别是转录因子 NFAT 和 RORγt 已知可激活 Il17a 转录，尽管其详细作用机制仍不完全清楚。在这里，我们表明核孤儿受体 NR2F6 可以减弱 NFAT 与 Il17a 基因启动子关键区域结合的能力。此外，由于 NR2F6 结合到 Il17a 基因座内的特定激素反应元件 (HRE)，它会干扰 RORγt 访问 DNA 的能力。一致地，在 Nr2f6 缺陷型 CD4(+) Th17 细胞中，Il17a 基因座内的 NFAT 和 RORγt 结合增强，但在 Nr2f6 过表达转基因 CD4(+) Th17 细胞中降低。总之，我们的研究结果揭示了通过 NR2F6 与 NFAT 和 RORγt 的直接相互作用对 Il17a 转录进行拮抗调节的一个例子。
