The orphan nuclear receptor RORα is a negative regulator of the inflammatory response
The orphan nuclear receptor RORα is a negative regulator of the inflammatory response
复制标题
DOI：
10.1093/embo-reports/kve007
复制
发表时间：
2001-01-01
期刊：
影响因子：
7.7
通讯作者：
Staels, B
中科院分区：
文献类型：
--
作者：
Delerive, P;Monté, D;Staels, B
类维生素A相关孤儿受体α（ROR α）（NR 1F 1）是核受体超家族的成员，其生物学功能在很大程度上未知。由于在ROR α基因中携带缺失的蹒跚小鼠患有免疫异常，我们产生了编码ROR α 1的腺病毒，以研究其在控制炎症反应中的潜在作用。我们证明ROR α在人原代平滑肌细胞中表达，并且ROR α 1的异位表达抑制TNF α诱导的IL-6、IL-8和考克斯-2在这些细胞中的表达。ROR α 1通过减少p65易位负性干扰NF-κ B信号通路，如通过蛋白质印迹、免疫染色和电泳迁移率变化测定所证明的。ROR α 1对NF-κ B的这种作用与I κ B α的诱导有关，I κ B α是NF-κ B信号通路的主要抑制蛋白，其表达被发现通过I κ B α启动子中的ROR应答元件被ROR α 1转录上调。总之，这些数据确定ROR α 1作为治疗慢性炎症性疾病（包括动脉粥样硬化和类风湿性关节炎）的潜在靶点。
Retinoid-related orphan receptor alpha (ROR alpha) (NR1F1) is a member of the nuclear receptor superfamily whose biological functions are largely unknown. Since staggerer mice, which carry a deletion in the ROR alpha gene, suffer from immune abnormalities, we generated an adenovirus encoding ROR alpha1 to investigate its potential role in control of the inflammatory response. We demonstrated that ROR alpha is expressed in human primary smooth-muscle cells and that ectopic expression of ROR alpha1 inhibits TNF alpha -induced IL-6, IL-8 and COX-2 expression in these cells. ROR alpha1 negatively interferes with the NF-kappaB signalling pathway by reducing p65 translocation as demonstrated by western blotting, immunostaining and electrophoretic mobility shift assays. This action of ROR alpha1 on NF-kappaB is associated with the induction of I kappaB alpha, the major inhibitory protein of the NF-kappaB signalling pathway, whose expression was found to be transcriptionally upregulated by ROR alpha1 via a ROR response element in the I kappaB alpha promoter. Taken together, these data identify ROR alpha1 as a potential target in the treatment of chronic inflammatory diseases, including atherosclerosis and rheumatoid arthritis.