Up-regulation of MicroRNA-155 in Macrophages Contributes to Increased Tumor Necrosis Factor α (TNFα) Production via Increased mRNA Half-life in Alcoholic Liver Disease
Up-regulation of MicroRNA-155 in Macrophages Contributes to Increased Tumor Necrosis Factor α (TNFα) Production via Increased mRNA Half-life in Alcoholic Liver Disease
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DOI：
10.1074/jbc.m110.145870
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发表时间：
2011-01-14
影响因子：
4.8
通讯作者：
Szabo, Gyongyi
中科院分区：
文献类型：
--
作者：
Bala, Shashi;Marcos, Miguel;Szabo, Gyongyi
肠源性脂多糖（LPS）和Toll样受体4（TLR 4）-LPS介导的TNF α产生增加对枯否细胞（KCs）的激活在酒精性肝病的发病机制中具有重要作用。micro-RNA（miR）-125b、miR-146 a和miR-155可以调节对LPS的炎症反应。在这里，我们评估了miR在酒精诱导的巨噬细胞活化中的参与。体外长期酒精处理导致RAW 264.7巨噬细胞中miR-155水平呈时间依赖性增加，但miR-125 b或miR-146 a水平未增加。此外，酒精预处理增强LPS诱导的巨噬细胞中miR-155的表达。我们发现酒精诱导的miR-155增加与TNF α诱导之间存在线性相关性。在酒精性肝病的小鼠模型中，我们发现与成对喂养的对照组相比，分离的KC中miR-155水平和TNF α的产生显著增加。miR-155在TNF α调节中的机制作用分别通过抑制miR-155后酒精处理的巨噬细胞中TNF α水平降低和miR-155过表达后TNF α产生增加来指示。我们发现miR-155影响TNF α mRNA的稳定性，因为miR-155抑制降低，而miR-155过表达增加TNF α mRNA的半衰期。使用NF-κ B抑制剂MG-132或Bay 11 -7082，我们证明NF-κ B激活介导了KC中酒精对miR-155的上调。总之，我们的新数据表明，长期饮酒通过NF-κ B增加巨噬细胞中的miR-155，增加的miR-155通过增加mRNA稳定性有助于酒精诱导的TNF α产生的升高。
Activation of Kupffer cells (KCs) by gut-derived lipopolysaccharide (LPS) and Toll-Like Receptors 4 (TLR4)-LPS-mediated increase in TNF alpha production has a central role in the pathogenesis of alcoholic liver disease. Micro-RNA (miR)-125b, miR-146a, and miR-155 can regulate inflammatory responses to LPS. Here we evaluated the involvement of miRs in alcohol-induced macrophage activation. Chronic alcohol treatment in vitro resulted in a time-dependent increase in miR-155 but not miR-125b or miR-146a levels in RAW 264.7 macrophages. Furthermore, alcohol pretreatment augmented LPS-induced miR-155 expression in macrophages. We found a linear correlation between alcohol-induced increase in miR-155 and TNF alpha induction. In a mouse model of alcoholic liver disease, we found a significant increase in both miR-155 levels and TNF alpha production in isolated KCs when compared with pair-fed controls. The mechanistic role of miR-155 in TNF alpha regulation was indicated by decreased TNF alpha levels in alcohol-treated macrophages after inhibition of miR-155 and by increased TNF alpha production after miR-155 overexpression, respectively. We found that miR-155 affected TNF alpha mRNA stability because miR-155 inhibition decreased whereas miR-155 overexpression increased TNF alpha mRNA half-life. Using the NF-kappa B inhibitors, MG-132 or Bay11-7082, we demonstrated that NF-kappa B activation mediated the up-regulation of miR-155 by alcohol in KCs. In conclusion, our novel data demonstrate that chronic alcohol consumption increases miR-155 in macrophages via NF-kappa B and the increased miR-155 contributes to alcohol-induced elevation in TNF alpha production via increased mRNA stability.