人类疾病往往是由于一些基因表达调控紊乱引起的。MicroRNA(miRNA)是近年来广为关注的重要的基因表达调控因子，在人类疾病的发生发展中起着重要作用。沈南教授领导的研究组整合上海交通大学附属仁济医院风湿科的临床优势和中国科学院上海生命科学研究院健康科学研究所的基础研究力量，近年来集中研究miRNA在系统性红斑狼疮中的作用，取得了一系列研究成果。2009年报道了miR-146a作为负反馈调节分子在狼疮关键致病通路中起了重要作用（Arthritis Rheum 2009），同期同刊附有专家评述，同时被faculty of 1000 medicine收录。今年又在国际学术期刊Journal of immunology发表了miRNA参与狼疮T细胞低甲基化调控的新机制，并被选为该期重点推荐的论文（In This Issue of the Journal of Immunology）。
近日，风湿病学领域最有影响力的杂志Arthritis Rheum.在线发表了有关miRNA参与狼疮炎症因子表达调控的最新研究成果：miR-125a能直接负向调节T细胞促RANTES分泌的主要转录因子klf13的表达，从而降低T细胞产生炎症性趋化因子RANTES的水平。狼疮病人外周血T细胞中miR-125a的水平明显低于正常人。患者T细胞激活后，KLF13和RANTES的表达水平较正常对照组相比也明显增高，当在病人T细胞中过表达miR-125a，可降低这一过程中KLF13和RANTES的表达。这些研究提示狼疮患者miR-125a表达缺陷可能是其体内RANTES水平异常升高的原因之一，miR-125a可能作为一个新的药物干预靶点，定向干预miR-125a的表达水平可发展为狼疮新的治疗手段。
该项工作得到国家科技部、国家自然科学基金和上海市科委的经费支持。
推荐原文出处：
Arthritis " Rheumatism DOI：10.1002/art.27632
MicroRNA-125a contributes to elevated inflammatory chemokine RANTES via targeting KLF13 in systemic lupus erythematosus
Xia Zhao, MD, Yuanjia Tang, PhD, Bo Qu, PhD, Huijuan Cui, MD, Shujun Wang, MD, Lijia Wang, MD, Xiaobing Luo, PhD, Xinfang Huang, MD, Jia Li, MD, Shunle Chen, MD, Nan Shen, MD *
Joint Molecular Rheumatology Laboratory of Institute of Health Sciences and Shanghai Renji Hospital, Shanghai JiaoTong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Objective.
MicroRNAs (miRNAs) have received increasing attention as post-transcriptional regulators that fine-tune the homeostasis of the inflammatory response. Our study aimed to clarify whether miR-125a, identified in a pilot expression profiling step, is involved in the inflammatory chemokine pathway in systemic lupus erythematosus (SLE).
Methods.
An independent verification of miR-125a expression in enlarged samples from SLE patients and normal controls was taken by the Taqman quantitative PCR. Combination of bioinformatics prediction and reporter gene assays was used to identify miR-125a targets. In vitro systems of overexpression by transfection and inducible expression by stimulation were performed to investigate the function of miR-125a, followed by real-time quantitative PCR and enzyme-linked immunosorbent assay.
Results.
The expression of miR-125a was reduced and the expression of its predicted target KLF13 was increased in SLE patients. Bioinformatics predictes miR-125a base-pairs with sequences in the 3'UTR of KLF13. Overexpression of miR-125a led to a significant reduction of RANTES and KLF13 expression. miR-125a inhibited endogenous KLF13 expression in a dose-dependent way, using gain- and loss-of- function methods. Luciferase reporter system confirmed the miR-125a binding sites. Notably, miR-125a expression was induced in T cells in a dose- and time-dependent manner. Finally, the introduction of miR-125a into lupus T cells alleviated the elevated RANTES expression.
Conclusion.
miR-125a negatively regulates RANTES expression by targeting KLF13 in activated T cells. The underexpression of miR-125a contributes to the elevated expression of RANTES in lupus. Our findings extend the role of miRNAs in the pathogenesis of lupus and provide potential strategies for therapeutic intervention
