MicroRNA-122 Inhibits the Production of Inflammatory Cytokines by Targeting the PKR Activator PACT in Human Hepatic Stellate Cells.
MicroRNA-122 Inhibits the Production of Inflammatory Cytokines by Targeting the PKR Activator PACT in Human Hepatic Stellate Cells.
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DOI：
10.1371/journal.pone.0144295
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Yokosuka O
中科院分区：
文献类型：
--
作者：
Nakamura M;Kanda T;Sasaki R;Haga Y;Jiang X;Wu S;Nakamoto S;Yokosuka O
MicroRNA-122 （miR-122）是肝脏中最丰富的miRs之一。先前的研究表明，miR-122在肝脏炎症中发挥作用，并在肝星状细胞（hsc）中发挥作用，肝星状细胞位于病变空间。在这里，我们发现，通过miR-122或靶向PACT的siRNA，短暂抑制pkr激活蛋白（PACT）的表达，抑制了人HSC LX-2中促炎细胞因子的产生，如白细胞介素(IL)-6、单核细胞趋化蛋白-1 （MCP-1）和IL-1β。序列和功能分析证实miR-122直接靶向PACT的3 ' -未翻译区。免疫荧光分析显示，miR-122阻断LX-2细胞中NF-κ b核易位。我们还发现，从转染mir -122的LX-2细胞中提取的条件培养基抑制了人单核细胞来源的THP-1细胞的迁移。综上所述，我们的研究表明miR-122可能下调造血干细胞和巨噬细胞趋化性中细胞因子的产生，并且靶向miR-122可能具有预防肝脏疾病进展的治疗潜力。
MicroRNA-122 (miR-122) is one of the most abundant miRs in the liver. Previous studies have demonstrated that miR-122 plays a role in inflammation in the liver and functions in hepatic stellate cells (HSCs), which reside in the space of Disse. Here, we showed that the transient inhibition of PKR-activating protein (PACT) expression, by miR-122 or siRNA targeting of PACT, suppressed the production of proinflammatory cytokines, such as interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1) and IL-1β, in human HSC LX-2. Sequence and functional analyses confirmed that miR-122 directly targeted the 3′-untranslated region of PACT. Immunofluorescence analysis revealed that miR-122 blocked NF-κB-nuclear translocation in LX-2 cells. We also showed that conditioned medium from miR-122-transfected LX-2 cells suppressed human monocyte-derived THP-1 cell migration. Taken together, our study indicates that miR-122 may downregulate cytokine production in HSCs and macrophage chemotaxis and that the targeting of miR-122 may have therapeutic potential for preventing the progression of liver diseases.