Oxidative stress, transcription factors and chromatin remodelling in lung inflammation
Oxidative stress, transcription factors and chromatin remodelling in lung inflammation
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DOI：
10.1016/s0006-2952(02)01153-x
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发表时间：
2002-09-01
影响因子：
5.8
通讯作者：
Rahman, I
中科院分区：
文献类型：
--
作者：
Rahman, I
氧化应激与几种炎症性肺疾病的发病机制有关。氧化剂和炎症介质如肿瘤坏死因子-α激活转录因子如核因子-kappaB和激活蛋白-1，从而导致促炎基因的表达。许多基因的表达，包括那些编码致炎介质的基因，都涉及由组蛋白蛋白提供的染色质结构的重塑。组蛋白乙酰化导致染色质结构解旋，从而允许转录因子进入启动子位置。核中组蛋白乙酰化是一个可逆的过程，受一组促进乙酰化的乙酰基转移酶(HATS)和促进去乙酰化的脱乙酰酶(HDACs)的调节。此外，几种共激活子、转录因子和核蛋白也具有组蛋白乙酰转移酶活性。肿瘤坏死因子-α和氧化剂过氧化氢(H_2O_2)共同改变组蛋白的乙酰化/去乙酰化，并激活核因子-kappaB和AP-1，导致人肺泡上皮细胞(A549)释放促炎细胞因子IL-8。药物抑制HDAC导致HAT活性、AP-1和NF-kappaB的激活，以及IL-8的释放。这表明，组蛋白乙酰化对染色质的重塑在氧化剂介导的肺部促炎反应中发挥了作用。(C)2002年，爱思唯尔科学公司出版。
Oxidative stress has been implicated in the pathogenesis of several inflammatory lung disorders. Oxidants and inflammatory mediators such as tumour necrosis factor-alpha (TNF-alpha) activate transcription factors such as nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) leading to the expression of pro-inflammatory genes. The expression of many genes, including those encoding pro-inflammatory mediators involves the remodelling of the chromatin structure provided by histone proteins. Histone acetylation causes the unwinding of chromatin structure therefore allowing transcription factor access to promoter sites. 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. In addition, several co-activators, transcription factors and nuclear proteins also have histone acetyltransferase activity. Both TNF-alpha and the oxidant, hydrogen peroxide (H2O2) alter histone acetylation/deacetylation, and the activation of NF-kappaB and AP-1, leading to the release of the pro-inflammatory cytokine interleukin-8 (IL-8) in human alveolar epithelial cells (A549). Pharmacological inhibition of HDAC leads to the increased HAT activity, AP-1 and NF-kappaB activation, and IL-8 release by H2O2 or TNF-alpha treatments. This suggests that the remodelling of chromatin by histone acetylation plays a role in the oxidant-mediated pro-inflammatory responses in the lungs. (C) 2002 Published by Elsevier Science Inc.