miR-125a调节系统性红斑狼疮患者T细胞炎症性趋化因子RANTES的表达  

miR-125a regulate RANTES expression in T cells from patients with systemic lupus erythematosus

作　　者：赵遐[1,2] 唐元家 曲波 崔慧娟 王树军[1,2] 王立珈[1,2] 黄新芳[1] 陈顺乐[1] 沈南[1,2] 

机构地区：[1]上海交通大学医学院附属仁济医院风湿科,上海市风湿病学研究所,上海200001 [2]中国科学院上海生命科学研究院/上海交通大学医学院,健康科学研究所分子风湿病学研究组,上海200025

出　　处：《现代免疫学》2010年第3期183-189,共7页Current Immunology

基　　金：国家自然科学基金重点资助项目(30830109);"重大新药创制"科技重大专项(2009ZX09503-009)

摘　　要：微小RNA(microRNA,miRNA)作为一种基因表达调控因子,在自身免疫性疾病中起重要作用。本研究旨在研究系统性红斑狼疮(SLE)患者中低表达的miR-125a基因在SLE炎症反应中的作用及其可能的作用机制。通过miRNA Taqman荧光定量聚合酶链反应(RT-PCR),发现同正常对照组相比,miR-125a表达水平在SLE患者中明显降低。生物信息学分析发现T淋巴细胞激活晚期促进RANTES分泌的主要转录因子KLF13是miR-125a的潜在靶基因。定量结果也表明,SLE患者中KLF13和RANTES水平正相关。从基因组DNA中克隆pri-miR-125a基因,构建miR-125a的表达载体。在HeLa细胞中过表达miR-125a能抑制内源性KLF13 mRNA的表达,反之亦然。报告基因系统实验证实,miR-125a能直接作用于KLF13的3′UTR区,从而调节KLF13的表达。进一步发现过表达miR-125a可以降低狼疮T细胞分泌RANTES的水平。我们的研究表明,miR-125a通过调节转录因子KLF13的表达而调节参与狼疮发病的炎性趋化因子RANTES的分泌。这提示定向干预miR-125a的表达水平可调节炎症性趋化因子RANTES的表达,从而发展为SLE新的治疗手段。Recent studies have implicated that microRNAs（miRNAs） contribute to the autoimmune diseases as a post-transcriptional modulators.In this study,we further investigated how the lower expression of miR-125a gene in patients with SLE would contribute to the dysregulation of inflammatory chemokines.It was found that the expression of miR-125a in SLE patients was significantly decreased compared with the healthy controls by using Taqman real time quantitative PCR.Bioinformatic algorithms predicted that KLF13,a key transcription factor regulated＂late＂expression of RANTES in T lymphocytes,and it could be served as a candidate target of miR-125a.Meanwhile,a positive correlation was found between KLF13 and RANTES expression.Furthermore,the endogenous expression of KLF13 mRNA was reduced or increased in a dose-dependent manner following miR-125a over-expression or inhibition,respectively.The reporter gene assays also approved that miR-125a directly targeted the 3＇UTR of KLF13.We found that miR-125a potentially alleviated high levels of RANTES in T cells from SLE patients,and it was down-regulated in SLE compared with healthy individuals.It is evident that restoration of the miR-125a expression in lupus patients may help to reduce RANTES expression and provide a new target for treatment or prevention of lupus.

关 键 词：系统性红斑狼疮 微小RNA miR-125a 趋化因子 

分 类 号：R392.11[医药卫生—免疫学]