Histone acetylation and deacetylation: importance in inflammatory lung diseases.
Inflammatory lung diseases are characterised by increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as nuclear factor-kappa B. Gene expression is regulated by acetylation of core histones through the action of coactivators, such as CREB-binding protein, with intrinsic histone acetyltransferase (HAT) activity. Conversely, gene repression is mediated via histone deacetylases (HDACs) and other corepressors. In asthma, there is an increase in HAT activity and some reduction in HDAC activity, which is restored by corticosteroid therapy. Corticosteroids switch off inflammatory genes in asthma through the inhibition of HAT activity and by the recruitment of HDAC2 to the activated inflammatory gene complex. In chronic obstructive pulmonary disease, there is a reduction in HDAC2 activity and expression, which may account for the amplified inflammation and resistance to the actions of corticosteroids. The reduction in HDAC2 may be secondary to oxidative and nitrative stress as a result of cigarette smoking and severe inflammation, and may also occur in severe asthma, smoking asthmatic patients and cystic fibrosis. Similar mechanisms may also account for the steroid resistance seen with latent adenovirus infections. The reduction in histone deacetylase activity can be restored by theophylline, which may be able to reverse steroid resistance in chronic obstructive pulmonary disease and other inflammatory diseases.
Barnes
P J
PJ
National Heart and Lung Institute, Imperial College, London SW3 6LY, UK. p.j.barnes@imperial.ac.uk
Adcock
I M
IM
Ito
K
K
D000107:Acetylation; D000123:Acetyltransferases / Q000737:chemistry / Q000378:metabolism*; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy / Q000201:enzymology; D001993:Bronchodilator Agents / Q000627:therapeutic use; D042002:Chromatin Assembly and Disassembly; D004351:Drug Resistance; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology; D011024:Pneumonia, Viral / Q000188:drug therapy / Q000201:enzymology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000201:enzymology; D012140:Respiratory Tract Diseases / Q000150:complications / Q000188:drug therapy / Q000201:enzymology*; D013806:Theophylline / Q000627:therapeutic use
D000305:Adrenal Cortex Hormones; D001993:Bronchodilator Agents; D006657:Histones; D013806:Theophylline; D000123:Acetyltransferases