Regulation of macrophage activation in alcoholic liver disease
Regulation of macrophage activation in alcoholic liver disease
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DOI：
10.1111/j.1440-1746.2006.04650.x
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发表时间：
2007-06-01
影响因子：
4.1
通讯作者：
Nagy, Laura E.
中科院分区：
文献类型：
--
作者：
Thakur, Varsha;McMullen, Megan R.;Nagy, Laura E.
慢性乙醇喂养使枯否细胞对脂多糖（LPS）激活敏感，导致肿瘤坏死因子α（TNF α）产生增加。TNF α合成的调节由转录和转录后机制通过响应于LPS暴露而激活的复杂信号转导途径的整合来控制。最近的数据表明，增加的LPS刺激的细胞外信号调节激酶途径1/2（ERK 1/2）的磷酸化是慢性乙醇在枯否细胞中的重要分子靶点之一。慢性乙醇暴露后ERK 1/2活化增加与Egr-1表达增加相关，Egr-1是慢性乙醇暴露后增强LPS刺激的TNF α mRNA表达所需的转录因子。Egr-1基因敲除小鼠在长期乙醇喂养后可避免脂肪肝损伤的发生，这表明Egr-1在慢性乙醇诱导的肝损伤的发生中起着重要作用。在这里，我们回顾了最近的研究，旨在了解慢性乙醇增强Kupffer细胞的LPS -> ERK 1/2 -> Egr-1 ->Tau NF α通路的机制。这些研究确定了烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶衍生的活性氧在慢性乙醇喂养后枯否细胞中ERK 1/2活化和随后TNF α产生中的关键作用。
Chronic ethanol feeding sensitizes Kupffer cells to activation by lipopolysaccharide (LPS), leading to increased production of tumor necrosis factor alpha (TNF alpha). The regulation of TNF alpha synthesis is controlled by both transcriptional and post-transcriptional mechanisms via the integration of complex signal transduction pathways activated in response to LPS exposure. Recent data has shown that increased LPS-stimulated phosphorylation of extracellular signal-regulated kinase pathway 1/2 (ERK1/2) is one of the important molecular targets of chronic ethanol in Kupffer cells. This increased activation of ERK1/2 after chronic ethanol is associated with increased expression of Egr-1, a transcription factor required for enhanced LPS-stimulated TNF alpha mRNA expression after chronic ethanol exposure. egr-1 null mice are protected from the development of fatty liver injury in response to chronic ethanol feeding, identifying an essential role for Egr-1 in the development of chronic ethanol-induced liver injury. Here we review recent studies aimed at understanding the mechanisms by which chronic ethanol enhances the LPS -> ERK1/2 -> Egr-1 ->Tau NF alpha pathway in Kupffer cells. These studies identify a critical role for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived reactive oxygen species in the activation of ERK1/2 and subsequent production of TNF alpha in Kupffer cells after chronic ethanol feeding.