11月10日, 國際權(quán)威學(xué)術(shù)期刊Journal of Immunology在線發(fā)表了中科院上海巴斯德所最新研究成果, 該成果揭示了microRNA在固有免疫中的作用以及調(diào)控機(jī)制, 并研究了這種作用在地塞米松抗炎癥效應(yīng)中的地位。這項成果是博士研究生朱清源在戈寶學(xué)研究員指導(dǎo)下完成的,。
(圖片來源：SIBS)
固有免疫中炎癥因子的調(diào)節(jié)需要被精細(xì)地控制, 過多或者過少的炎癥因子都可能會造成機(jī)體的負(fù)面反應(yīng). MAPK是負(fù)責(zé)炎癥因子產(chǎn)生的重要信號通路, 可以在TLR激活的免疫反應(yīng)中通過磷酸化來誘導(dǎo)下游轉(zhuǎn)錄因子激活炎癥因子轉(zhuǎn)錄。而同時,這個信號通路的激活會導(dǎo)致MKP-1的產(chǎn)生,,，這是一種可以通過對MAPK進(jìn)行去磷酸化作用使炎癥反應(yīng)下調(diào)的分子。 MAPK與MKP-1構(gòu)成了一個標(biāo)準(zhǔn)的負(fù)反饋調(diào)節(jié)莖環(huán)結(jié)構(gòu),。
研究人員發(fā)現(xiàn)一種microRNA (miR-101)可以通過靶向MKP-1 mRNA的3’- UTR來調(diào)節(jié)MAPK的反應(yīng), 進(jìn)而影響下游炎癥因子的分泌,。更進(jìn)一步的實驗表明, PI3K/AKT通路可以調(diào)控miR-101的表達(dá), 從而影響MKP-1以及MAPK的表達(dá)和活化情況, 這表示P3IK/AKT通路可以通過miR-101與MAPK通路進(jìn)行串?dāng)_. 研究發(fā)現(xiàn)，在地塞米松的抗炎癥作用中, miR-101被抑制,，至少部分是因為地塞米松導(dǎo)致MKP-1大幅度上調(diào)而降低了MAPK活化作用. 這項研究為今后對細(xì)胞因子分泌引起的免疫疾病的治療策略提供了新的靶標(biāo),。
此項研究成果得到科技部、國家自然科學(xué)基金,、上海市科學(xué)技術(shù)委員會和中國科學(xué)院的資金資助,，并已經(jīng)申請了相關(guān)專利。（生物谷Bioon.com）
生物谷推薦英文摘要：
The Journal of Immunology, 2010, doi:10.4049/jimmunol.1000798
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.
