Redox Regulation of Histone Deacetylases and Glucocorticoid-Mediated Inhibition of the Inflammatory Response

Abstract

Gene expression, at least in part, is regulated by changes in histone acetylation status induced by activation of the proinflammatory redox-sensitive transcription factors activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB). Hyperacetylated histone is associated with open actively transcribed DNA and enhanced inflammatory gene expression. In contrast, hypoacetylated histone is linked to a closed repressed DNA state and a lack of gene expression. The degree of inflammatory gene expression is a result of a balance between histone acetylation and histone deacetylation. One of the major mechanisms of glucocorticoid function is to recruit histone deacetylase enzymes to the site of active gene expression, thus reducing inflammation. Oxidative stress can enhance inflammatory gene expression by further stimulating AP-1- and NF-kappaB-mediated gene expression and elevating histone acetylation. In addition, oxidants can reduce glucocorticoid function by attenuating histone deacetylase activity and expression. Thus, oxidant stress, acting through changes in chromatin structure, can enhance inflammation and induce a state of relative glucocorticoid insensitivity. This may account for the lack of glucocorticoid sensitivity in patients with chronic obstructive pulmonary disease. Antioxidants should reduce the inflammation and restore glucocorticoid sensitivity in these subjects.