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首页> 美国卫生研究院文献>Frontiers in Pharmacology >TNF-α-Induced cPLA2 Expression via NADPH Oxidase/Reactive Oxygen Species-Dependent NF-κB Cascade on Human Pulmonary Alveolar Epithelial Cells
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TNF-α-Induced cPLA2 Expression via NADPH Oxidase/Reactive Oxygen Species-Dependent NF-κB Cascade on Human Pulmonary Alveolar Epithelial Cells

机译：NADPH氧化酶/活性氧依赖的NF-κB级联在人肺泡上皮细胞上的TNF-α诱导的cPLA2表达

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Tumor necrosis factor-α (TNF-α) triggers activation of cytosolic phospholipase A2 (cPLA2) and then enhancing the synthesis of prostaglandin (PG) in inflammatory diseases. However, the detailed mechanisms of TNF-α induced cPLA2 expression were not fully defined in human pulmonary alveolar epithelial cells (HPAEpiCs). We found that TNF-α-stimulated increases in cPLA2 mRNA (5.2 folds) and protein (3.9 folds) expression, promoter activity (4.3 folds), and PGE2 secretion (4.7 folds) in HPAEpiCs, determined by Western blot, real-time PCR, promoter activity assay and PGE2 ELISA kit. These TNF-α-mediated responses were abrogated by the inhibitors of NADPH oxidase [apocynin (APO) and diphenyleneiodonium chloride (DPI)], ROS [N-acetyl cysteine, (NAC)], NF-κB (Bay11-7082) and transfection with siRNA of ASK1, p47phox, TRAF2, NIK, IKKα, IKKβ, or p65. TNF-α markedly stimulated NADPH oxidase activation and ROS including superoxide and hydrogen peroxide production which were inhibited by pretreatment with a TNFR1 neutralizing antibody, APO, DPI or transfection with siRNA of TRAF2, ASK1, or p47phox. In addition, TNF-α also stimulated p47phox phosphorylation and translocation in a time-dependent manner. On the other hand, TNF-α induced TNFR1, TRAF2, ASK1, and p47phox complex formation in HPAEpiCs, which were attenuated by a TNF-α neutralizing antibody. We found that pretreatment with NAC, DPI, or APO also attenuated the TNF-α-stimulated IKKα/β and NF-κB p65 phosphorylation, NF-κB (p65) translocation, and NF-κB promoter activity in HPAEpiCs. Finally, we observed that TNF-α-stimulated NADPH oxidase activation and ROS generation activates NF-κB through the NIK/IKKα/β pathway. Taken together, our results demonstrated that in HPAEpiCs, up-regulation of cPLA2 by TNF-α is, at least in part, mediated through the cooperation of TNFR1, TRAF2, ASK1, and NADPH oxidase leading to ROS generation and ultimately activates NF-κB pathway.
机译：肿瘤坏死因子-α（TNF-α）触发细胞质磷脂酶A2（cPLA2）的激活，然后增强炎症性疾病中前列腺素（PG）的合成。但是，TNF-α诱导的cPLA2表达的详细机制在人肺泡上皮细胞（HPAEpiCs）中尚未完全确定。我们发现，TNF-α刺激了HPAEpiCs中cPLA2 mRNA（5.2倍）和蛋白质（3.9倍）表达，启动子活性（4.3倍）和PGE2分泌（4.7倍）的增加，这是通过蛋白质印迹，实时PCR确定的，启动子活性测定和PGE2 ELISA试剂盒。这些TNF-α介导的反应被NADPH氧化酶[apocynin（APO）和diphenyleneiodonium chloride（DPI）]，ROS [N-乙酰半胱氨酸（NAC）]，NF-κB（Bay11-7082）和转染的抑制剂废除带有ASK1，p47 phox ，TRAF2，NIK，IKKα，IKKβ或p65的siRNA。 TNF-α显着刺激了NADPH氧化酶的活化和ROS，包括超氧化物和过氧化氢的产生，这些活性被TNFR1中和抗体，APO，DPI预处理或用TRAF2，ASK1或p47 phox 的siRNA转染所抑制。此外，TNF-α还以时间依赖性方式刺激p47 phox 的磷酸化和易位。另一方面，TNF-α诱导HPAEpiCs中TNFR1，TRAF2，ASK1和p47 phox 复合物的形成，并被TNF-α中和抗体减弱。我们发现，使用NAC，DPI或APO进行预处理还可以减弱TNF-α刺激的IKKα/β和NF-κBp65磷酸化，NF-κB（p65）易位以及HPAEpiCs中的NF-κB启动子活性。最后，我们观察到TNF-α刺激的NADPH氧化酶激活和ROS生成通过NIK /IKKα/β途径激活NF-κB。两者合计，我们的结果表明，在HPAEpiC中，TNF-α对cPLA2的上调至少部分是通过TNFR1，TRAF2，ASK1和NADPH氧化酶的合作介导的，从而导致ROS的产生并最终激活NF-κB。途径。

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