MCPIP1 alleviated lipopolysaccharide-induced liver injury by regulating SIRT1 via modulation of microRNA-9
MCPIP1 alleviated lipopolysaccharide-induced liver injury by regulating SIRT1 via modulation of microRNA-9
复制标题
MCPIP1 通过调节 microRNA 来调节 SIRT1，减轻脂多糖诱导的肝损伤 -9
DOI：
10.1002/jcp.28809
复制
发表时间：
2019-12-01
影响因子：
5.6
通讯作者：
Hu, Dahai
中科院分区：
文献类型：
--
作者：
Han, Shichao;Li, Zhenzhen;Hu, Dahai
脓毒症的严重程度与过度的炎症反应有关。MCP-1诱导蛋白(MCPIP1)通过去泛素化肿瘤坏死因子受体相关因子K48或K63的多泛素，对炎症反应起负性调节作用。MCPIP1在炎症负调控中的作用已为人所知，然而，只有确切的分子途径尚不清楚。本研究的目的是探讨MCPIP1是否以及如何参与脂多糖(LPS)诱导的肝损伤的调节。用脂多糖诱导巨噬细胞和小鼠模型。采用实时定量聚合酶链式反应、免疫印迹、细胞转染、双荧光素酶报告实验、酶联免疫吸附实验、苏木精-伊红染色等体外检测方法，探讨MCPIP1的作用以及MCPIP1、Sirtuin 1(SIRT1)和microRNA-9(miR-9)之间的相互作用。我们发现在内毒素诱导的库普弗细胞和RAW 264.7巨噬细胞中，MCPIP1水平升高，SIRT1水平下降。MCPIP1过表达可减轻细胞因子分泌和p65核转位。进一步的研究表明，MCPIP1通过促进SIRT1的表达来控制p65的乙酰化，从而调控p65的核转位。同时，我们发现miR-9可以通过与SIRT1信使RNA的3‘-非翻译区结合来直接调控SIRT1的转录，而miR-9受MCPIP1的负调控。重要的是，体内过表达MCPIP1可以减轻内毒素诱导的炎症反应和脓毒症小鼠的肝损伤。这些结果表明，MCPIP1通过促进SIRT1的表达而减轻炎症反应和脓毒症相关的肝损伤，miR-9参与了MCPIP1介导的SIRT1的调节。总之，我们的结果提供了一个可能的新的信号轴，涉及内毒素诱导的脓毒症小鼠的MCPIP1/miR-9/SIRT1。
The severity of sepsis is associated with excessive inflammatory responses. MCP-1 induced protein (MCPIP1) could negatively regulate inflammatory responses by deubiquitinating K48 or K63 polyubiquitins of TNF receptor-associated factors. The function of MCPIP1 in negative regulation of inflammation is known, however, only the exact molecular pathway remains unknown. The aim of this study was to investigate whether and how MCPIP1 is involved in the regulation of lipopolysaccharides (LPS)-induced liver injury. Macrophages and a mouse model were induced by LPS treatment. Several in vitro assays, such as quantitative real-time PCR, immunoblotting, cell transfection, dual luciferase reporter assay, Enzyme-linked immunosorbent assay, and Hematoxylin-Eosin staining assay were used to explore the role of MCPIP1 and the interaction between MCPIP1, Sirtuin 1 (SIRT1), and microRNA-9 (miR-9). We found that the level of MCPIP1 increased and the level of SIRT1 decreased in LPS induced Kupffer cells or RAW 264.7 macrophages. Overexpression of MCPIP1 alleviated cytokine secretion and p65 nuclear translocation. Further study showed that MCPIP1 regulated p65 nuclear translocation by controlling p65 acetylation via promoting SIRT1 expression. Meanwhile, we found that miR-9 could directly regulate SIRT1 transcription by binding to the 3 '-Untranslated Region of SIRT1 messenger RNA and that miR-9 was negatively regulated by MCPIP1. Importantly, overexpression of MCPIP1 in vivo could alleviate LPS-induced inflammation responses and liver injury in septic mice. These results demonstrated that MCPIP1 could alleviate inflammation responses and sepsis associated liver injury by promoting the expression of SIRT1, and miR-9 was involved in the MCPIP1-mediated regulation of SIRT1. Collectively, our results provide a possible novel signaling axis involving MCPIP1/miR-9/SIRT1 in LPS-induced septic mice.