Glucocorticoids are by far the most effective anti-inflammatory therapy for asthma (and many other inflammatory diseases). Glucocorticoids bind to glucocorticoid receptors in the cytoplasm and translocate to the nucleus, where they interact as dimers with glucocorticoid response elements in the promoter region of steroid-sensitive genes to switch on transcription of anti-inflammatory genes, (such as MKP-1). This involves binding of GR to coactivator proteins and acetylation of core histones, particularly histone-4 through the intrinsic histone acetyltransferase (HAT) activity of these coactivators. But most of the anti-inflammatory effects of glucocorticoids are mediated via suppression of inflammatory genes. These have been activated by pro-inflammatory transcription factors, such as nuclear factor-kB and activator protein-1, through histone-4 acetylation (with a different acetylation pattern from glucocorticoid-mediated activation). Activated GR interacts with coactivators associated with inflammatory genes (such as cytokines) and directly inhibits their HAT activity, but more importantly recruits histone deacetylase(HDAC)2 to the hyperacetylated inflammatory gene complex and thereby shuts down transcription.
In COPD and asthma patients who smoke glucocorticoids fail to suppress inflammation. This appears to be due to a loss of HDAC2 activity and expression as a result of oxidative and nitrative stress. We are able to restore both HDAC activity and steroid responsiveness in alveolar macrophages from COPD patients by transfecting the cells with HDAC2 and by low concentrations of theophylline, an HDAC activator which markedly potentiates the anti-inflammatory actions of glucocorticoids. This may lead to new approaches in management of chronic inflammatory diseases, particularly in situations where glucocorticoids appear to have lost their efficacy.
Barnes PJ, Adcock IM. How do corticosteroids work in asthma? Ann Intern Med 2003; 139:359-70.
Barnes PJ, Ito K, Adcock IM. A mechanism of corticosteroid resistance in COPD: inactivation of histone deacetylase. Lancet 2004; 363:731-3.
Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ. Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med 2004; 200:689-95.
04 - 06 Apr 2005
British Endocrine Societies