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© 2004 The American Thoracic Society
Glucocorticoids
Effects on Gene Transcription
Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College, London, United Kingdom
Correspondence and requests for reprints should be addressed to Ian M. Adcock, Ph.D., Department of Thoracic Medicine, National Heart and Lung Institute, Dovehouse St, London SW3 6LY, UK. E-mail: ian.adcock{at}ic.ac.uk
The major antiinflammatory effects of glucocorticoids appear to be due largely to interaction between the activated glucocorticoid receptor and transcription factors, notably nuclear factor-
B (NF-B) and activator protein-1, that mediate the expression of inflammatory genes. NF-B switches on inflammatory genes via a process involving recruitment of transcriptional coactivator proteins and changes in chromatin modifications such as histone acetylation. This process must occur in the correct temporal manner to allow for effective inflammatory gene expression to occur. Glucocorticoids, using a similar mechanism, are also able to switch on a number of antiinflammatory genes. An important question is why glucocorticoids switch off only inflammatory genes, as they clearly do not suppress all activated genes and are well tolerated as long-term treatments. The interactions between NF-B and the glucocorticoid receptor result in differing effects on histone acetylation and deacetylation. Oxidative stress due to cigarette smoke may be an important factor in inducing glucocorticoid resistance in chronic obstructive pulmonary disease and may involve changes in histone acetylation/deacetylation balance.
Key Words: asthma • chronic obstructive pulmonary disease • histone acetylation/deacetylation • glucocorticoid resistance • nuclear factor-B
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