Article

Redox modulation of chromatin remodeling: impact on histone acetylation and deacetylation, NF-kappaB and pro-inflammatory gene expression.

Department of Environmental Medicine, Division of Lung Biology and Disease, University of Rochester Medical Center, NY, USA.
Biochemical Pharmacology (Impact Factor: 4.65). 10/2004; 68(6):1255-67. DOI: 10.1016/j.bcp.2004.05.042
Source: PubMed

ABSTRACT Reactive oxygen species (ROS), either directly or via the formation of lipid peroxidation products, such as 4-hydroxy-2-nonenal, acrolein and F2-isoprostanes, may play a role in enhancing inflammation through the activation and phosphorylation of stress kinases (JNK, ERK, p38) and redox-sensitive transcription factors such as NF-kappaB and AP-1. This increases the expression of genes regulating a battery of distinct pro-inflammatory mediators. Acetylation by histone acetyltransferase (HAT) of specific lysine residues on the N-terminal tail of core histones, results in uncoiling of the DNA and increased accessibility to transcription factor binding. In contrast, histone deacetylation by histone deacetylase (HDAC) represses gene transcription by promoting DNA winding thereby limiting access to transcription factors. Oxidative stress activates NF-kappaB resulting in expression of pro-inflammatory mediators through the activation of intrinsic HAT activity on co-activator molecules. In addition, oxidative stress also inhibits HDAC activity and in doing so enhances inflammatory gene expression which leads to a chronic inflammatory response. Oxidative stress can also increase complex formation between the co-activator CBP/p300 and the p65 subunit of NF-kappaB suggesting a further role of oxidative stress in chromatin remodeling. The antioxidant and/or anti-inflammatory effects of thiol molecules (glutathione, N-acetyl-L-cysteine and N-acystelyn), dietary polyphenols (curcumin-diferuloylmethane and resveratrol), the bronchodilator theophylline and glucocorticoids have all been shown to play a role in either controlling NF-kappaB activation or chromatin remodeling through modulation of HDAC activity and subsequently inflammatory gene expression in lung epithelial cells. Thus, oxidative stress regulates both signal transduction and chromatin remodeling which in turn impacts on pro-inflammatory responses in the lungs.

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