MiR-34a inhibits lipopolysaccharide-induced inflammatory response through targeting Notch1 in murine macrophages
MiR-34a inhibits lipopolysaccharide-induced inflammatory response through targeting Notch1 in murine macrophages
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MiR-34a 通过靶向小鼠巨噬细胞中的 Notch1 抑制脂多糖诱导的炎症反应
DOI：
10.1016/j.yexcr.2012.03.018
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发表时间：
2012-06-10
影响因子：
3.7
通讯作者：
Chu, Yiwei
中科院分区：
文献类型：
--
作者：
Jiang, Pei;Liu, Ronghua;Chu, Yiwei
炎症反应是宿主免疫系统对抗入侵病原体时发生的复杂事件，这是一把双刃剑，需要适当的控制。 MicroRNA (miRNA) 作为一层新的基因调控机制而出现，据报道对炎症具有至关重要的影响。在当前的研究中，我们发现 miR-34a（之前因其强大的肿瘤抑制作用而闻名）是一种新型炎症调节剂。我们发现，在脂多糖（LPS）刺激后，巨噬细胞中 miR-34a 的表达下调。 LPS处理的RAW264.7细胞中，miR-34a模拟物减少，而miR-34a的抑制增加，炎症细胞因子肿瘤坏死因子-α（lTNF-α）和白介素-6（IL-6）的表达。生物信息学预测揭示了Notch1 3'非翻译区（UTR）中miR-34a的潜在结合位点，并通过荧光素酶测定进一步证实。此外，在RAW264.7中，Notch1的mRNA和蛋白水平均被miR-34a下调。随后，通过遗传或药理学抑制敲低 Notch1，对 LPS 诱导的巨噬细胞炎症反应表现出与 miR-34a 模拟物相似的效果。此外，LPS 诱导的 NF-κ B 激活也被 miR-34a 显着抑制。这些结果首次共同确定了 miR-34a 作为 LPS 诱导炎症的负调节因子，至少部分是通过靶向 Notch1 实现的。除了将 miR-34a 从肿瘤抑制因子扩展到炎症调节因子之外，这项研究还表明，能够增强 miR-34a 表达的化合物或 miR-34a 本身可能在抗炎药物开发中具有前景 (C) 2012 Elsevier Inc. 保留所有权利。
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.