期刊
MOLECULAR AND CELLULAR BIOCHEMISTRY
卷 234, 期 1, 页码 239-248出版社
SPRINGER
DOI: 10.1023/A:1015905010086
关键词
oxidant; TNF-alpha; GSH; AP-1; NF-kappa B; histone acetylation; deacetylases; alveolar epithelial cells
类别
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.
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