Oxidative stress, transcription factors and chromatin remodelling in lung inflammation.
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.
Rahman
Irfan
I
ELEGI & Colt Research Laboratory, MRC Centre for Inflammation Research, Medical School, University of Edinburgh, Wilkie Building, Teviot Place, Edinburgh, UK. ir@srv1.med.ed.ac.uk
D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D002843:Chromatin / Q000502:physiology*; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D018384:Oxidative Stress / Q000502:physiology*; D011014:Pneumonia / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*
D002843:Chromatin; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases