Oxidative stress and TNF-α induce histone acetylation and NF-κB/AP-1 activation in alveolar epithelial cells:: Potential mechanism in gene transcription in lung inflammation
Oxidative stress and TNF-α induce histone acetylation and NF-κB/AP-1 activation in alveolar epithelial cells:: Potential mechanism in gene transcription in lung inflammation
复制标题
DOI：
10.1023/a:1015905010086
复制
发表时间：
2002-05-01
影响因子：
4.3
通讯作者：
MacNee, W
中科院分区：
文献类型：
--
作者：
Rahman, I;Gilmour, PS;MacNee, W
氧化剂和炎症介质如肿瘤坏死因子- α (tnf - α)激活核因子κ B （nf - κ B）和激活蛋白-1 （AP-1）转录因子，增强促炎和保护性抗氧化基因的表达。染色质在细胞核内的重塑是由DNA盘绕的组蛋白核心上的组蛋白残基的乙酰化/去乙酰化程度所控制的，这对于转录因子DNA结合和基因转录是非常重要的。DNA的解绕对于允许转录因子DNA结合和基因转录是重要的。核组蛋白乙酰化是一个可逆过程，由一组促进乙酰化的乙酰转移酶（HATs）和促进去乙酰化的去乙酰化酶（HDACs）调节。本研究的目的是确定氧化应激和促炎介质tnf - α是否改变组蛋白乙酰化/去乙酰化以及NF-kappaB和AP-1的激活，从而导致人肺泡上皮细胞中促炎细胞因子IL-8的释放（A549）。过氧化氢（H2O2） （100 μ m）和tnf - α (10 ng/ml)对A549细胞造成氧化应激，表现为抗氧化剂还原性谷胱甘肽（GSH）的消耗，同时氧化谷胱甘肽（GSSG）水平升高。与未处理的细胞相比，H2O2、tnf - α和HDAC抑制剂trichostatin A、TSA （100 ng/ml）处理A549细胞后，细胞免疫染色显示组蛋白乙酰化程度显著增加，HAT活性增加。H2O2、tnf - α和TSA都增加了NF-kappaB和AP-1 DNA结合到它们的共识位点上。TSA处理增强了A549细胞中H2O2或tnf - α处理产生的AP-1和NF-kappaB结合的增加。H2O2和tnf - α均显著增加了IL-8的释放，与单独处理相比，TSA预处理A549细胞进一步增强了IL-8的释放。本研究表明，氧化剂H2O2和促炎介质tnf - α诱导组蛋白乙酰化，从而降低GSH水平，增加AP-1和NF-kappaB激活，从而增加肺泡上皮细胞中促炎IL-8的释放。这表明了氧化应激的促炎作用的机制。
Oxidants and inflammatory mediators such as tumour necrosis factor-alpha (TNF-alpha) activate nuclear factor kappa B (NF-kappaB) and activator protein-1 (AP-1) transcription factors, and enhance the expression of both pro-inflammatory and protective antioxidant genes. Remodelling of chromatin within the nucleus, controlled by the degree of acetylation/deacetylation of histone residues on the histone core around which DNA is coiled, is important in allowing access for transcription factor DNA binding and hence gene transcription. Unwinding of DNA is important in allowing access for transcription factor DNA binding and hence gene transcription. Nuclear histone acetylation is a reversible process, and is regulated by a group of acetyltransferases (HATs) which promote acetylation, and deacetylases (HDACs) which promote deacetylation. The aim of this study was to determine whether oxidative stress and the pro-inflammatory mediator, TNF-alpha, altered histone acetylation/deacetylation and the activation of NF-kappaB and AP-1, leading to the release of the pro-inflammatory cytokine IL-8 in human alveolar epithelial cells (A549). Hydrogen peroxide (H2O2) (100 muM) and TNF-alpha (10 ng/ml) imposed oxidative stress in A549 cells as shown by depletion of the antioxidant reduced glutathione (GSH) concomitant with increased levels of oxidised glutathione (GSSG). Treatment of A549 cells with H2O2, TNF-alpha and the HDAC inhibitor, trichostatin A, TSA (100 ng/ml) significantly increased acetylation of histone proteins shown by immunostaining of cells and increased HAT activity, compared to the untreated cells. H2O2, and TNF-alpha, and TSA all increased NF-kappaB and AP-1 DNA binding to their consensus sites assessed by the electrophoretic mobility shift assay. TSA treatment potentiated the increased AP-1 and NF-kappaB binding, produced by H2O2 or TNF-alpha treatments in A549 cells. Both H2O2 and TNF-alpha significantly increased IL-8 release, which was further enhanced by pre-treatment of A549 cells with TSA compared to the individual treatments. This study shows that the oxidant H2O2 and the pro-inflammatory mediator, TNF-alpha induce histone acetylation which is associated with decreased GSH levels and increased AP-1 and NF-kappaB activation leading to enhanced proinflammatory IL-8 release in alveolar epithelial cells. This indicates a mechanism for the pro-inflammatory effects of oxidative stress.