Arachidonic acid stimulates TNFα production in Kupffer cells via a reactive oxygen species-pERK1/2-Egr1-dependent mechanism
Arachidonic acid stimulates TNFα production in Kupffer cells via a reactive oxygen species-pERK1/2-Egr1-dependent mechanism
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DOI：
10.1152/ajpgi.00465.2011
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发表时间：
2012-07-01
影响因子：
4.5
通讯作者：
Nieto, Natalia
中科院分区：
文献类型：
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作者：
Cubero, Francisco Javier;Nieto, Natalia
Cubero FJ，Nieto N.花生四烯酸通过活性氧-pERK 1/2-Egr 1依赖性机制刺激枯否细胞产生TNF α美国生理学胃肠和肝脏生理学杂志303：G228-G239，2012年。首次发表于2012年4月26日; doi：10.1152/ajpgi.00465.2011。枯否细胞是酒精诱导的肝损伤介质的关键来源，如活性氧、趋化因子、生长因子和类花生酸。由于富含多不饱和脂肪酸的饮食是酒精性肝病发展的必要条件，我们假设多不饱和脂肪酸可以与乙醇协同作用，促进枯否细胞活化和TNF α产生，从而导致肝损伤。初级枯否细胞从控制和乙醇喂养的大鼠培养花生四烯酸表现出类似的增殖率比未处理的细胞，但是，花生四烯酸诱导的表型变化，脂质过氧化，氢过氧化物和超氧自由基的产生。在人类枯否细胞中也发生了类似的作用。这些事件在乙醇喂养的大鼠的枯否细胞中更大，抗氧化剂和花生四烯酸代谢抑制剂阻止了它们。花生四烯酸处理增加NADPH氧化酶活性。NADPH氧化酶和花生四烯酸代谢的抑制剂部分防止氧化应激的增加。在花生四烯酸刺激后，TNF α迅速而持续地增加，这在乙醇喂养大鼠的枯否细胞中比对照大鼠的枯否细胞中更大。花生四烯酸诱导ERK 1/2磷酸化和早期生长反应蛋白1（Egr 1）核转位，乙醇与花生四烯酸协同促进这一作用。PD 98059（一种促分裂原细胞外激酶1/2抑制剂）和姜黄素（一种Egr 1抑制剂）可阻断花生四烯酸介导的枯否细胞TNF α上调。这项研究揭示了花生四烯酸和乙醇增加枯否细胞中TNF α产生的机制，从而导致酒精性肝病。
Cubero FJ, Nieto N. Arachidonic acid stimulates TNF alpha production in Kupffer cells via a reactive oxygen species-pERK1/2-Egr1-dependent mechanism. Am J Physiol Gastrointest Liver Physiol 303: G228-G239, 2012. First published April 26, 2012; doi:10.1152/ajpgi.00465.2011.-Kupffer cells are a key source of mediators of alcohol-induced liver damage such as reactive oxygen species, chemokines, growth factors, and eicosanoids. Since diets rich in polyunsaturated fatty acids are a requirement for the development of alcoholic liver disease, we hypothesized that polyunsaturated fatty acids could synergize with ethanol to promote Kupffer cell activation and TNF alpha production, hence, contributing to liver injury. Primary Kupffer cells from control and from ethanol-fed rats incubated with arachidonic acid showed similar proliferation rates than nontreated cells; however, arachidonic acid induced phenotypic changes, lipid peroxidation, hydroperoxides, and superoxide radical generation. Similar effects occurred in human Kupffer cells. These events were greater in Kupffer cells from ethanol-fed rats, and antioxidants and inhibitors of arachidonic acid metabolism prevented them. Arachidonic acid treatment increased NADPH oxidase activity. Inhibitors of NADPH oxidase and of arachidonic acid metabolism partially prevented the increase in oxidant stress. Upon arachidonic acid stimulation, there was a rapid and sustained increase in TNF alpha, which was greater in Kupffer cells from ethanol-fed rats than in Kupffer cells from control rats. Arachidonic acid induced ERK1/2 phosphorylation and nuclear translocation of early growth response-1 (Egr1), and ethanol synergized with arachidonic acid to promote this effect. PD98059, a mitogen extracellular kinase 1/2 inhibitor, and curcumin, an Egr1 inhibitor, blocked the arachidonic acid-mediated upregulation of TNF alpha in Kupffer cells. This study unveils the mechanism whereby arachidonic acid and ethanol increase TNF alpha production in Kupffer cells, thus contributing to alcoholic liver disease.