Effects of glucocorticoids on gene transcription

• Published in: European journal of pharmacology 2004-10, Vol.500 (1), p.51-62
• Main Authors: Hayashi, Ryuji, Wada, Hiroo, Ito, Kazuhiro, Adcock, Ian M.
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Asthma; Asthma - drug therapy; Asthma - metabolism; Biological and medical sciences; Chromatin Assembly and Disassembly - genetics; Glucocorticoid resistance; Glucocorticoids - pharmacology; Histone acetylation/deacetylation; Humans; Inflammation - drug therapy; Inflammation - genetics; Inflammation - metabolism; Medical sciences; NF-kappa B - metabolism; Nuclear factor-κB; Pharmacology. Drug treatments; Receptors, Glucocorticoid - agonists; Receptors, Glucocorticoid - physiology; Transcription, Genetic - drug effects
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2004.07.011

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-κB (NF-κB) and activator protein-1 (AP-1), that mediate the expression of inflammatory genes. NF-κB 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-κB and the glucocorticoid receptor result in differing effects on histone modifications and chromatin remodelling. Drugs that enhance glucocorticoid receptor nuclear translocation (long acting β-agonists) and GR-associated histone deacetylases activity (theophylline) have been shown to be effective add-on therapies. In addition, dissociated glucocorticoids that target NF-κB preferentially have also been successful in the treatment of allergic disease.