Glucocorticoid-regulated transcription factors.
Glucocorticoids are the most effective antiinflammatory drugs used in the treatment of asthma. They act by binding to a specific receptor (GR) that, upon activation, translocates to the nucleus and either increases (transactivates) or decreases (transrepresses) gene expression. Inhibition of pro-inflammatory transcription factors such as activator protein (AP)-1, signal transducers and activators of transcription (STATs), nuclear factor of activated T cells (NFAT) and nuclear factor (NF)-kappa B is thought to be a major action of glucocorticoids. Acetylation of histones allows unwinding of the local DNA structure and enables RNA polymerase II to enhance gene transcription. Histone acetylation is regulated by a balance between the activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs). GR acts as a direct inhibitor of NF-kappa B-induced HAT activity and also by recruiting HDAC2 to the NF-kappa B/HAT complex. A sub-group of patients with glucocorticoid-insensitive asthma have an inability to induce histone acetylation in response to dexamethasone suggesting reduced expression of a GR-specific HAT. This suggests that pharmacological manipulation of specific histone acetylation status is a potentially useful approach for the treatment of inflammatory diseases. Identification of the precise mechanism by which activated GR recruits HDAC2 may reveal new targets for the development of drugs that may dissociate the antiinflammatory actions of glucocorticoids from their side effects that are largely due to gene induction.
Adcock
I M
IM
Thoracic Medicine, National Heart & Lung Institute, Imperial College of Science, Technology & Medicine, Dovehouse Street, London SW3 6LY, UK. ian.adcock@ic.ac.uk
D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology*; D002454:Cell Differentiation / Q000276:immunology; D004351:Drug Resistance; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D007962:Leukocytes / Q000276:immunology; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D015398:Signal Transduction; D013601:T-Lymphocytes; D014157:Transcription Factors / Q000096:biosynthesis* / Q000494:pharmacology; D015533:Transcriptional Activation
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D006655:Histone Deacetylases