Effects of glucocorticoids on gene transcription.
Glucocorticoids bind to and activate a cytoplasmic glucocorticoid receptor. The activated glucocorticoid receptor translocates into the nucleus and binds to specific response elements in the promoter regions of anti-inflammatory genes such as lipocortin-1 and secretory leukocyte protease inhibitor (SLPI). However, the major anti-inflammatory effects of glucocorticoids appear to be due largely to interaction between the activated glucocorticoid receptor and transcription factors, notably nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), that mediate the expression of inflammatory genes. NF-kappaB switches on inflammatory genes via a process involving recruitment of transcriptional co-activator 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. The interactions between NF-kappaB and the glucocorticoid receptor result in differing effects on histone modifications and chromatin remodelling. Drugs that enhance glucocorticoid receptor nuclear translocation (long acting beta-agonists) and GR-associated histone deacetylases activity (theophylline) have been shown to be effective add-on therapies. In addition, dissociated glucocorticoids that target NF-kappaB preferentially have also been successful in the treatment of allergic disease.
Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College, Dovehouse St, London, SW3 6LY, UK.
Ryuji
R
Hayashi
Hiroo
H
Wada
Kazuhiro
K
Ito
Ian M
IM
Adcock
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects*
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid