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CORRESPONDENCE: P. J. Barnes, Dept of Thoracic Medicine, National Heart and Lung Institute, Dovehouse St, London, SW3 6LY, UK. Fax: 44 2073515675. E-mail: p.j.barnes{at}imperial.ac.uk
Keywords: Glucocorticoid receptor, glucocorticosteroid, steroid resistance, transcription factor
Received: November 1, 2004
Accepted February 21, 2005
Corticosteroids are the most effective anti-inflammatory therapy for asthma. Inflammation in asthma is characterised by the increased expression of multiple inflammatory genes regulated by pro-inflammatory transcription factors, such as nuclear factor-
Activated glucocorticoid receptors also bind to recognition sites in the promoters of certain genes in order to activate their transcription, resulting in secretion of anti-inflammatory proteins, such as mitogen-activated protein kinase phosphatase-1, which inhibits mitogen-activated protein kinase signalling pathways. Glucocorticoid receptors may also interact with other recognition sites to inhibit transcription, for example of several genes linked to their side-effects.
In some patients with steroid-resistant asthma, there are abnormalities in glucocorticoid receptor signalling pathways. In chronic obstructive pulmonary disease patients and asthmatic patients who smoke, histone deacetylase 2 is markedly impaired as a result of oxidative/nitrative stress, and so inflammation is resistant to the anti-inflammatory effects of corticosteroids.
The therapeutic implications of these new findings are discussed.
B and activator protein-1, which bind to and activate coactivator molecules that acetylate core histones and switch on gene transcription. Corticosteroids suppress the multiple inflammatory genes that are activated in asthmatic airways, mainly by reversing histone acetylation of activated inflammatory genes through binding of glucocorticoid receptors to coactivators and recruitment of histone deacetylase 2 to the activated transcription complex.
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