Ethanol augments RANTES/CCL5 expression in rat liver sinusoidal endothelial cells and human endothelial cells via activation of NF-kappa B, HIF-1 alpha, and AP-1.
Ethanol augments RANTES/CCL5 expression in rat liver sinusoidal endothelial cells and human endothelial cells via activation of NF-kappa B, HIF-1 alpha, and AP-1.
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DOI：
10.4049/jimmunol.0901564
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发表时间：
2009-11-01
期刊：
影响因子：
--
通讯作者：
Kalra VK
中科院分区：
文献类型：
--
作者：
Yeligar SM;Machida K;Tsukamoto H;Kalra VK
长期饮酒会导致肝脏炎症和肝硬变。酒精性肝病患者肝脏RANTES/CCL5水平升高。然而，关于乙醇诱导RANTES上调的分子机制知之甚少。在本研究中，我们观察到乙醇喂养的大鼠肝窦内皮细胞(E-rLSECs)RANTES和缺氧诱导因子-1α(HIF-1α)mRNAs的表达是对照组(C-rLSECs)的几倍。急性乙醇处理分离的rLSECs和人真皮微血管内皮细胞也有类似的效果。乙醇诱导的RANTES基因表达需要乙醇代谢、p38MAPK、HIF-1α和JNK-2，而不需要JNK-1。EMSA实验显示，乙醇使缺氧诱导因子-1α与RANTES启动子内的野生型缺氧反应元件(−31至−9)结合增加。RANTES启动子分析表明，乙醇介导的RANTES表达需要转录起始点附近的顺式元件Hre-1(NT−22~−19)、Hre-2(NT−32~−29)和AP-1(NT−250~−244)。染色质免疫沉淀实验证实了这些结果，表明HIF-1α与hRE-1结合增强。此外，启动子分析显示，c-jun、c-jun/c-Fos和Jund而不是JunB与RANTES启动子的AP-1位点结合。乙醇介导的NF-RANTES B激活可导致κ-1α的激活和RANTES的表达。与乙醇喂养的对照组小鼠相比，乙醇喂养的c-Junflx/Flox-Mx-1-Cre小鼠血浆中RANTES的表达水平降低，支持c-jun在乙醇诱导的RANTES表达中的作用。我们的研究表明，乙醇介导的RANTES/CCL5的表达是通过HIF-1α的激活而发生的，而不依赖于低氧。HIF-1、α和AP-1在乙醇诱导的RANTES表达中的识别为减轻乙醇诱导的炎症反应提供了新的策略。
Chronic alcohol consumption leads to liver inflammation and cirrhosis. Alcoholic liver disease patients have increased levels of hepatic RANTES/CCL5. However, less is known about the molecular mechanisms for ethanol-induced RANTES up-regulation. In this study, we observed that liver sinusoidal endothelial cells derived from ethanol-fed rats (E-rLSECs) showed severalfold increases in RANTES and hypoxia-inducible factor 1α (HIF-1α) mRNAs compared with control rLSECs (C-rLSECs). Similar effects were seen in acute ethanol treatment of isolated rLSECs and human dermal microvascular endothelial cells. Ethanol-induced RANTES mRNA expression required ethanol metabolism, p38 MAPK, HIF-1α, and JNK-2, but not JNK-1. EMSA experiments showed increased HIF-1α binding to wild-type hypoxia response elements (HREs; −31 to −9 bp) within the RANTES promoter in response to ethanol. RANTES promoter analysis showed that cis elements proximal to the transcription start site, HRE-1 (nt −22 to −19), HRE-2 (nt −32 to −29), and AP-1 (nt −250 to −244) were required for ethanol-mediated RANTES expression. These results were corroborated by chromatin immunoprecipitation assays showing augmented HIF-1α binding to HRE-1. Additionally, promoter analysis revealed c-Jun, c-Jun/c-Fos, and JunD, but not JunB, bound to the AP-1 site of the RANTES promoter. Ethanol-mediated activation of NF-κB led to HIF-1α activation and concomitant RANTES expression. Plasma of ethanol-fed c-Junflox/flox-Mx-1-Cre mice showed attenuated levels of RANTES compared with ethanol-fed control mice, supporting the role of c-Jun in ethanol-induced RANTES expression. Our studies showed that ethanol-mediated RANTES/CCL5 expression occurs via HIF-1α activation independently of hypoxia. The identification of HIF-1α and AP-1 in ethanol-induced RANTES expression provides new strategies to ameliorate ethanol-induced inflammatory responses.
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