Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation
Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation
复制标题
肝脏 X 受体 (LXR) 介导小鼠和人类 Th17 分化的负调节。
DOI：
10.1172/jci42974
复制
发表时间：
2011-02-01
影响因子：
15.9
通讯作者：
Zang, Ying Qin
中科院分区：
文献类型：
--
作者：
Cui, Guoliang;Qin, Xia;Zang, Ying Qin
Th 17细胞是CD 4 +T细胞的一个亚群，在清除某些细菌和真菌病原体方面具有重要作用。然而，它们也与自身免疫性疾病如多发性硬化症有关。幼稚CD 4 +T细胞暴露于IL-6和TGF-β通过其中涉及许多蛋白质的过程导致Th 17细胞分化。我们在这里报告，肝脏X受体（LXR）的异位表达抑制小鼠CD 4 +T细胞的Th 17极化，而LXR缺陷促进Th 17分化在体外。在多发性硬化症的实验性自身免疫性脑脊髓炎（EAE）模型中，小鼠中的LXR激活改善了疾病，而LXR缺乏则加重了疾病。进一步的分析表明，由LXR靶基因编码的Srebp-1通过与IL 17启动子上的E-box元件结合，与芳烃受体（Ahr）物理相互作用并抑制Ahr控制的IL 17转录来介导Th 17分化的抑制。Ahr的PAS结构域和Srebp-1的N端酸性区域是这种相互作用的关键。另外的分析表明，类似的LXR依赖性机制在体外人Th 17分化过程中是可操作的。这项研究报告了我们认为是一种新的信号通路LXR介导的调节Th 17细胞分化和自身免疫。
Th17 cells are a subset of CD4+T cells with an important role in clearing certain bacterial and fungal pathogens. However, they have also been implicated in autoimmune diseases such as multiple sclerosis. Exposure of naive CD4+T cells to IL-6 and TGF-β leads to Th17 cell differentiation through a process in which many proteins have been implicated. We report here that ectopic expression of liver X receptor (LXR) inhibits Th17 polarization of mouse CD4+T cells, while LXR deficiency promotes Th17 differentiation in vitro. LXR activation in mice ameliorated disease in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, whereas LXR deficiency exacerbated disease. Further analysis revealed that Srebp-1, which is encoded by an LXR target gene, mediated the suppression of Th17 differentiation by binding to the E-box element on theIl17promoter, physically interacting with aryl hydrocarbon receptor (Ahr) and inhibiting Ahr-controlledIl17transcription. The putative active site (PAS) domain of Ahr and the N-terminal acidic region of Srebp-1 were essential for this interaction. Additional analyses suggested that similar LXR-dependent mechanisms were operational during human Th17 differentiation in vitro. This study reports what we believe to be a novel signaling pathway underlying LXR-mediated regulation of Th17 cell differentiation and autoimmunity.