Targeting the epigenome in the treatment of asthma and chronic obstructive pulmonary disease.
Epigenetic modification of gene expression by methylation of DNA and various post-translational modifications of histones may affect the expression of multiple inflammatory genes. Acetylation of histones by histone acetyltransferases activates inflammatory genes, whereas histone deacetylation results in inflammatory gene repression. Corticosteroids exert their antiinflammatory effects partly by inducing acetylation of antiinflammatory genes, but mainly by recruiting histone deacetylase-2 (HDAC2) to activated inflammatory genes. HDAC2 deacetylates acetylated glucocorticoid receptors so that they can suppress activated inflammatory genes in asthma. In chronic obstructive pulmonary disease (COPD), there is resistance to the antiinflammatory actions of corticosteroids, which is explained by reduced activity and expression of HDAC2. This can be reversed by a plasmid vector, which restores HDAC2 levels, but may also be achieved by low concentrations of theophylline. Oxidative stress causes corticosteroid resistance by reducing HDAC2 activity and expression by activation of phosphoinositide-3-kinase-delta, resulting in HDAC2 phosphorylation via a cascade of kinases. Theophylline reverses corticosteroid resistance by directly inhibiting oxidant-activated PI3Kdelta and is mimicked by PI3Kdelta knockout or by selective inhibitors. Other treatments may also interact in this pathway, making it possible to reverse corticosteroid resistance in patients with COPD, as well as in smokers with asthma and some patients with severe asthma in whom similar mechanisms operate. Other histone modifications, including methylation, tyrosine nitration, and ubiquitination may also affect histone function and inflammatory gene expression, and better understanding of these epigenetic pathways could led to novel antiinflammatory therapies, particularly in corticosteroid-resistant inflammation.
Barnes
Peter J
PJ
National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse St., London SW3 6LY, UK. p.j.barnes@imperial.ac.uk
D000107:Acetylation; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D004351:Drug Resistance / Q000502:physiology; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000276:immunology
D000305:Adrenal Cortex Hormones; D006657:Histones; D006655:Histone Deacetylases