人類疾病往往是由于一些基因表達(dá)調(diào)控紊亂引起的,。MicroRNA(miRNA)是近年來廣為關(guān)注的重要的基因表達(dá)調(diào)控因子,，在人類疾病的發(fā)生發(fā)展中起著重要作用。沈南教授領(lǐng)導(dǎo)的研究組整合上海交通大學(xué)附屬仁濟醫(yī)院風(fēng)濕科的臨床優(yōu)勢和中國科學(xué)院上海生命科學(xué)研究院健康科學(xué)研究所的基礎(chǔ)研究力量,，近年來集中研究miRNA在系統(tǒng)性紅斑狼瘡中的作用,，取得了一系列研究成果。2009年報道了miR-146a作為負(fù)反饋調(diào)節(jié)分子在狼瘡關(guān)鍵致病通路中起了重要作用（Arthritis Rheum 2009）,，同期同刊附有專家評述,，同時被faculty of 1000 medicine收錄。今年又在國際學(xué)術(shù)期刊Journal of immunology發(fā)表了miRNA參與狼瘡T細(xì)胞低甲基化調(diào)控的新機制,，并被選為該期重點推薦的論文（In This Issue of the Journal of Immunology）,。
近日，風(fēng)濕病學(xué)領(lǐng)域最有影響力的雜志Arthritis Rheum.在線發(fā)表了有關(guān)miRNA參與狼瘡炎癥因子表達(dá)調(diào)控的最新研究成果：miR-125a能直接負(fù)向調(diào)節(jié)T細(xì)胞促RANTES分泌的主要轉(zhuǎn)錄因子klf13的表達(dá),，從而降低T細(xì)胞產(chǎn)生炎癥性趨化因子RANTES的水平,。狼瘡病人外周血T細(xì)胞中miR-125a的水平明顯低于正常人?；颊逿細(xì)胞激活后,，KLF13和RANTES的表達(dá)水平較正常對照組相比也明顯增高，當(dāng)在病人T細(xì)胞中過表達(dá)miR-125a,，可降低這一過程中KLF13和RANTES的表達(dá),。這些研究提示狼瘡患者miR-125a表達(dá)缺陷可能是其體內(nèi)RANTES水平異常升高的原因之一，miR-125a可能作為一個新的藥物干預(yù)靶點,，定向干預(yù)miR-125a的表達(dá)水平可發(fā)展為狼瘡新的治療手段,。
該項工作得到國家科技部、國家自然科學(xué)基金和上海市科委的經(jīng)費支持。(生物谷Bioon.com)
生物谷推薦原文出處：
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
