Molecular mechanisms of corticosteroid actions.
Glucocorticoids are the most effective therapeutic agents used for the treatment of chronic inflammatory diseases of the lung. They act by interacting with, and thereby activating, a specific cytoplasmic receptor (GR) which then migrates to the cell nucleus and inhibits inflammatory gene transcription. Inflammatory gene transcription is enhanced by activation of several intracellular signalling pathways which activate transcription factor such as NF-kappaB and AP-1. These transcription factors bind to DNA and induce local unwinding of the DNA structure allowing increased gene transcription. Glucocorticoids interfere with the ability of NF-kappaB and AP-1 to induce transcription by increasing the compaction of unwound chromosomal DNA in a process that involves deacetylation of histone proteins. A small number of asthmatic patients are resistant to the beneficial effects of glucocorticoids. This defect does not appear to be due to a reduced expression of GR but may be associated with a failure of GR to translocate into the nucleus and/or a reduced ability to inhibit AP-1 actions.
Payne
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Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse Street, London SW3 6 LY, UK.
Adcock
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D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D004351:Drug Resistance; D005260:Female; D005938:Glucocorticoids / Q000235:genetics* / Q000494:pharmacology*; D006801:Humans; D008171:Lung Diseases / Q000175:diagnosis / Q000188:drug therapy; D008297:Male; D008967:Molecular Biology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010597:Pharmacogenetics; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014157:Transcription Factors