J.Immunology：揭示microRNA在固有免疫中的作用

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11月10日, 国际权威学术期刊Journal of Immunology在线发表了中科院上海巴斯德所最新研究成果, 该成果揭示了microRNA在固有免疫中的作用以及调控机制, 并研究了这种作用在地塞米松抗炎症效应中的地位。这项成果是博士研究生朱清源在戈宝学研究员指导下完成的。

固有免疫中炎症因子的调节需要被精细地控制, 过多或者过少的炎症因子都可能会造成机体的负面反应. MAPK是负责炎症因子产生的重要信号通路, 可以在TLR激活的免疫反应中通过磷酸化来诱导下游转录因子激活炎症因子转录。而同时,这个信号通路的激活会导致MKP-1的产生,，这是一种可以通过对MAPK进行去磷酸化作用使炎症反应下调的分子。 MAPK与MKP-1构成了一个标准的负反馈调节茎环结构。

研究人员发现一种microRNA (miR-101)可以通过靶向MKP-1 mRNA的3’- UTR来调节MAPK的反应, 进而影响下游炎症因子的分泌。更进一步的实验表明, PI3K/AKT通路可以调控miR-101的表达, 从而影响MKP-1以及MAPK的表达和活化情况, 这表示P3IK/AKT通路可以通过miR-101与MAPK通路进行串扰. 研究发现，在地塞米松的抗炎症作用中, miR-101被抑制，至少部分是因为地塞米松导致MKP-1大幅度上调而降低了MAPK活化作用. 这项研究为今后对细胞因子分泌引起的免疫疾病的治疗策略提供了新的靶标。

此项研究成果得到科技部、国家自然科学基金、上海市科学技术委员会和中国科学院的资金资助，并已经申请了相关专利。

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MicroRNA-101 Targets MAPK Phosphatase-1 To Regulate the Activation of MAPKs in Macrophages

Qing-Yuan Zhu,*, Qin Liu, Jian-Xia Chen,* Ke Lan,* and Bao-Xue Ge*,

*Institute Pasteur of Shanghai, Chinese Academy of Sciences, Graduate School of Chinese Academy of Sciences, and The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, China

MAPK phosphatase-1 (MKP-1) is an archetypical member of the dual-specificity phosphatase family that deactivates MAPKs. Induction of MKP-1 has been implicated in attenuating the LPS- or peptidoglycan-induced biosynthesis of proinflammatory cytokines, but the role of noncoding RNA in the expression of the MKP-1 is still poorly understood. In this study, we show that MKP-1 is a direct target of microRNA-101 (miR-101). Transfection of miR-101 attenuates induction of MKP-1 by LPS as well as prolonged activation of p38 and JNK/stress-activated protein kinase, whereas inhibition of miR-101 enhances the expression of MKP-1 and shortens p38 and JNK activation. We also found that expression of miR-101 is induced by multiple TLR ligands, including LPS, peptidoglycan, or polyinosinic-polycytidylic acid, and that inhibition of PI3K/Akt by LY294002 or Akt RNA interference blocks the induction of miR-101 by LPS in RAW264.7 macrophage cells. Moreover, treatment of cells with dexamethasone, a widely used anti-inflammatory agent, markedly inhibits miR-101 expression and enhances the expression of MKP-1 in LPS-stimulated macrophages. Together, these results indicate that miR-101 regulates the innate immune responses of macrophages to LPS through targeting MKP-1.