Nuclear receptor Nur77 suppresses inflammatory response dependent on COX-2 in macrophages induced by oxLDL
Nuclear receptor Nur77 suppresses inflammatory response dependent on COX-2 in macrophages induced by oxLDL
复制标题
核受体Nur77抑制oxLDL诱导的巨噬细胞中依赖于COX-2的炎症反应
DOI：
10.1016/j.yjmcc.2010.03.023
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发表时间：
2010-08-01
影响因子：
5
通讯作者：
He, Ben
中科院分区：
文献类型：
--
作者：
Shao, Qin;Shen, Ling-Hong;He, Ben
氧化型低密度脂蛋白（oxLDL）与巨噬细胞发生交互作用，两者在动脉粥样硬化的发生和发展中起着至关重要的作用。孤儿核受体Nur 77在巨噬细胞中被各种刺激强烈诱导，表明它可能是血管细胞炎症的关键调节因子。Nur 77在oxLDL诱导的巨噬细胞中的活化和随后的功能的详细机制仍不清楚。在这项研究中，我们证明，Nur 77是上调的剂量和时间依赖性的方式，oxLDL刺激小鼠巨噬细胞，通过实时PCR和蛋白质印迹检测。oxLDL激活ERK 1/2和p38 MAPK的磷酸化，抑制p38 MAPK而不抑制ERK 1/2则减弱Nur 77的表达。重要的是，Nur 77的过表达抑制oxLDL诱导的促炎细胞因子和趋化因子分泌，包括肿瘤坏死因子（TNF）α和单核细胞趋化蛋白-1（MCP-1）。而用特异性小干扰RNA（siRNA）敲低Nur 77的表达则导致分泌增强。此外，巨噬细胞暴露于oxLDL显着上调环氧合酶-2（考克斯-2）的表达。然而，这可以被Nur 77过表达显著抑制。此外，Nur 77 siRNA增加oxLDL诱导的考克斯-2表达，6-巯基嘌呤（6-MP）减弱了这种增加。结果表明，Nur 77通过p38 MAPK信号通路被oxLDL诱导，随后通过抑制活化的巨噬细胞中的促炎性考克斯-2通路来保护炎症。特异性修饰Nur 77的转录活性可能是预防和治疗动脉粥样硬化的潜在分子靶点。(C)2010爱思唯尔有限公司保留所有权利。
Oxidized low-density lipoprotein (oxLDL) cross-talks with macrophages, and both play a crucial role in the initiation and progression of atherosclerosis. Orphan nuclear receptor Nur77 is potently induced in macrophages by diverse stimuli, suggesting that it may be a key regulator of inflammation in vascular cells. The detailed mechanism of Nur77 activation and subsequent function in macrophages induced by oxLDL remains unclearly. In this study, we demonstrated that Nur77 is upregulated in a dose and time-dependent fashion by oxLDL stimulation in murine macrophages, as detected by real-time PCR and Western blotting. OxLDL activated the phosphorylation ERK1/2 and p38 MAPK, inhibition of p38 MAPK but not ERK1/2 attenuated Nur77 expression. Importantly, overexpression of Nur77 suppressed oxLDL-induced proinflammatory cytokines and chemokines secretion including tumor necrosis factor (TNF)alpha and monocyte chemoattractant protein-1(MCP-1). While knockdown Nur77 expression by specific small interfering RNA (siRNA) resulted in the enhancement of the secretion. Furthermore, exposure of macrophages to oxLDL significantly upregulated cyclooxygenase-2(COX-2) expression. However, this could be markedly inhibited by Nur77 overexpression. Also, Nur77 siRNA increased oxLDL-induced COX-2 expression and 6-mercaptopurine (6-MP) attenuated the increase. The results indicated that Nur77 is induced by oxLDL via p38 MAPK signal pathway and subsequently protects against inflammation by the inhibition of proinflammatory COX-2 pathway in activated macrophages. Specifically modifying transcription activity of Nur77 may represent a potential molecular target for the prevention and treatment of atherosclerosis. (C) 2010 Elsevier Ltd. All rights reserved.