Histone deacetylase-2 and airway disease.
The increased expression of inflammatory genes in inflammatory lung diseases is regulated by acetylation of core histones, whereas histone deacetylase-2 (HDAC2) suppresses inflammatory gene expression. Corticosteroids suppress inflammatory genes in asthma by inhibiting histone acetyltransferase and in particular by recruiting HDAC2 to the nuclear factor-kappaB-activated inflammatory gene complex. This involves deacetylation of the acetylated glucocorticoid receptor. In COPD, severe asthma and asthmatics who smoke, HDAC2 is reduced, thus preventing corticosteroids from suppressing inflammation. The reduction in HDAC2 appears to be secondary to increased oxidative and nitrative stress in the lungs. Antioxidants and inhibitors of nitric oxide synthesis may therefore restore corticosteroid sensitivity in COPD, but this can also be achieved by low concentrations of theophylline and curcumin, which act as HDAC activators. Theophylline is a direct inhibitor of oxidant-activated phosphoinositide-3-kinase-delta, which is involved in inactivation of HDAC2. In the future selective PI3Kdelta inhibitors and more direct activators of HDAC2 may be used to treat corticosteroid-resistant inflammatory diseases of the lung, including COPD, severe asthma and asthma in smokers.
Barnes
Peter J
PJ
National Heart & Lung Institute, Imperial College, London, UK. p.j.barnes@imperial.ac.uk
D001249:Asthma / Q000235:genetics* / Q000503:physiopathology; D004351:Drug Resistance / Q000502:physiology; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000502:physiology; D005938:Glucocorticoids / Q000494:pharmacology*; D056464:Histone Deacetylase 2 / Q000235:genetics*; D006801:Humans; D008171:Lung Diseases / Q000235:genetics / Q000503:physiopathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000503:physiopathology
D005938:Glucocorticoids; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2