MiR-34a inhibits lipopolysaccharide-induced inflammatory response through targeting Notch1 in murine macrophages

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• 作者：Pei Jiang^a ; ^b ; ¹ ; Ronghua Liu^a ; ^b ; ¹ ; Yijie Zheng^a ; ^b ; Xiaoming Liu^a ; Lijun Chang^a ; Shudao Xiong^a ; ^c ; Yiwei Chu^a ; ^b ; ^{yiwei_chu@126.com}
• 关键词：MicroRNA ; miR-34a ; Notch1 ; Macrophage ; Inflammation
• 刊名：Experimental Cell Research
• 出版年：2012
• 期刊代码：292_00144827
• 类别：med
• 出版时间：10 June, 2012
• 卷：318
• 期：10
• 页码：1175-1184
• 文件大小：1083 K

摘要

Inflammatory responses are complex events occurring when the host immune system fights against invading pathogens, which are double-edged swords requiring appropriate control. MicroRNAs (miRNAs), emerging as a new layer of gene-regulation mechanism, have been reported to have crucial effects on inflammation. In the current study, we identified miR-34a, previously known for its potent tumor suppressive role, to be a novel inflammation regulator. We found that the expression of miR-34a was downregulated in macrophages after lipopolysaccharide (LPS) stimulation. MiR-34a mimics decreased, while the inhibition of miR-34a increased, the expression of inflammatory cytokines tumor necrosis factor-<alpha > (TNF-<alpha >) and interleukin-6 (IL-6) in LPS treated RAW264.7 cells. Bioinformatics predictions revealed a potential binding site of miR-34a in 3鈥?untranslated region (UTR) of Notch1 and it was further confirmed by luciferase assay. Moreover, both the mRNA and protein level of Notch1 were downregulated by miR-34a in RAW264.7. Subsequently, knockdown of Notch1 with either genetic or pharmacological inhibition exhibited similar effects as miR-34a mimics on LPS-induced macrophage inflammatory response. Furthermore, the NF-魏B activation induced by LPS was also significantly suppressed by miR-34a. These results together identify, for the first time, miR-34a as a negative regulator in LPS-induced inflammation at least partially by targeting Notch1. Besides extending the knowledge of miR-34a from tumor suppressor to inflammation regulator, this study also provides an implication that compounds which can enhance miR-34a expression or miR-34a itself may hold a promise in anti-inflammatory drugs development.