microRNA-181a represses ox-LDL-stimulated inflammatory response in dendritic cell by targeting c-Fos.
microRNA-181a represses ox-LDL-stimulated inflammatory response in dendritic cell by targeting c-Fos.
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microRNA-181a 通过靶向 c-Fos 抑制树突状细胞中 ox-LDL 刺激的炎症反应
DOI：
10.1194/jlr.m028878
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发表时间：
2012-11
影响因子：
6.5
通讯作者：
Ge J
中科院分区：
文献类型：
--
作者：
Wu C;Gong Y;Yuan J;Zhang W;Zhao G;Li H;Sun A;KaiHu;Zou Y;Ge J
氧化型低密度脂蛋白（ox-LDL）激活树突状细胞（DCs），从而引发动脉粥样硬化的炎症反应，但调节机制尚不清楚。microRNAs（miRNAs）是DC功能的重要调节因子。本研究评估了miRNAs对ox-LDL诱导的DC免疫应答的调节。在高脂血症ApoE缺陷小鼠的CD 11 c + DCs中，microRNA miR-181 a显著上调。在体外培养的骨髓来源的DC（BMDCs）中，ox-LDL可促进DC成熟并上调miR-181 a的表达。miR-181 a的表达降低ox-LDL诱导的CD 83和CD 40表达，抑制IL-6和TNF-α的分泌，上调IL-10（一种重要的抗炎细胞因子，被ox-LDL抑制）。内源性miR-181 a的抑制逆转了对CD 83和CD 40的作用以及对IL-6和TNF-α的作用。通过基因本体评估评估miR-181 a的推定靶基因，并鉴定c-Fos介导的炎症通路。荧光素酶实验证明miR-181 a靶向于c-Fos mRNA的3′非翻译区。因此，miR-181 a的丰度降低了BMDC中的c-Fos蛋白，而miR-181 a的抑制增加了BMDC中的c-Fos蛋白。因此，我们认为miR-181 a通过靶向DC中的c-Fos来减弱ox-LDL刺激的免疫炎症反应。
Oxidized LDL (ox-LDL) activates dendritic cells (DCs), thereby initiating inflammation responses in atherosclerosis, yet the modulatory mechanisms remain unclear. MicroRNAs (miRNAs) are important regulators for DC functions. This study evaluated the regulation by miRNAs of the ox-LDL-induced DC immune response. In CD11c+ DCs from ApoE-deficient mice with hyperlipidemia, microRNA miR-181a was significantly up-regulated. In cultured bone marrow-derived DCs (BMDCs), ox-LDL promoted DC maturation and up-regulated miR-181a expression. Abundance of miR-181a attenuated ox-LDL-induced CD83 and CD40 expression, inhibited the secretion of interleukin (IL)-6 and TNF-α, and up-regulated IL-10, an important anti-inflammatory cytokine that was inhibited by ox-LDL. Inhibition of the endogenous miR-181a reversed the effects on CD83 and CD40 as well as the effects on IL-6 and TNF-α. The putative target genes of miR-181a were evaluated by gene ontology assessment, and the c-Fos-mediated inflammation pathway was identified. miR-181a targeted the 3′ untranslated region of c-Fos mRNA by luciferase experiments. Thus, abundance of miR-181a reduced c-Fos protein, whereas inhibition of miR-181a increased c-Fos protein in BMDCs. We therefore suggest that miR-181a attenuates ox-LDL-stimulated immune inflammation responses by targeting c-Fos in DCs.