期刊
EXPERIMENTAL CELL RESEARCH
卷 318, 期 10, 页码 1175-1184出版社
ELSEVIER INC
DOI: 10.1016/j.yexcr.2012.03.018
关键词
MicroRNA; miR-34a; Notch1; Macrophage; Inflammation
资金
- National 973 project in China [2011CB910404]
- National Science Foundation of China [30872378, 81072408]
- Science and Technology Commission of Shanghai Municipality in China [10JC1401100]
- Graduates Creation Foundation of Fudan University [EYF101107]
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 (lTNF-alpha) and interleukin-6 (IL-6) in LPS treated RAW264.7 cells. Bioinformatics predictions revealed a potential binding site of miR-34a in 3' 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-kappa 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 (C) 2012 Elsevier Inc. All rights reserved.
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