title: Corticosteroid effects on cell signalling.
abstract: Corticosteroids are the most effective anti-inflammatory therapy for asthma. Inflammation in asthma is characterised by the increased expression of multiple inflammatory genes regulated by pro-inflammatory transcription factors, such as nuclear factor-kappaB and activator protein-1, which bind to and activate coactivator molecules that acetylate core histones and switch on gene transcription. Corticosteroids suppress the multiple inflammatory genes that are activated in asthmatic airways, mainly by reversing histone acetylation of activated inflammatory genes through binding of glucocorticoid receptors to coactivators and recruitment of histone deacetylase 2 to the activated transcription complex. Activated glucocorticoid receptors also bind to recognition sites in the promoters of certain genes in order to activate their transcription, resulting in secretion of anti-inflammatory proteins, such as mitogen-activated protein kinase phosphatase-1, which inhibits mitogen-activated protein kinase signalling pathways. Glucocorticoid receptors may also interact with other recognition sites to inhibit transcription, for example of several genes linked to their side-effects. In some patients with steroid-resistant asthma, there are abnormalities in glucocorticoid receptor signalling pathways. In chronic obstructive pulmonary disease patients and asthmatic patients who smoke, histone deacetylase 2 is markedly impaired as a result of oxidative/nitrative stress, and so inflammation is resistant to the anti-inflammatory effects of corticosteroids. The therapeutic implications of these new findings are discussed.
authors.affiliation: Dept of Thoracic Medicine, National Heart and Lung Institute, Dovehouse St, London, SW3 6LY, UK. p.j.barnes@imperial.ac.uk
authors.forename: P J
authors.initials: PJ
authors.lastname: Barnes
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy*; D015815:Cell Adhesion Molecules / Q000235:genetics; D002843:Chromatin / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D004351:Drug Resistance; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D015815:Cell Adhesion Molecules; D002843:Chromatin; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D018343:Receptors, Adrenergic, beta-2; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors