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Histone deacetylase-2 and airway diseaseNational Heart & Lung Institute, Imperial College, London, UK, p.j.barnes{at}imperial.ac.uk
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-
Key Words: antioxidant • curcumin • histone acetylation • histone deacetylase • phosphoinositide-3-kinase • theophylline
This version was published on October
1, 2009 Therapeutic Advances in Respiratory Disease, Vol. 3, No. 5,
235-243 (2009) |
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B-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-
, which is involved in inactivation of HDAC2. In the future selective PI3K