Glucocorticoids: effects on gene transcription.
The major antiinflammatory 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, that mediate the expression of inflammatory genes. NF-kappaB switches on inflammatory genes via a process involving recruitment of transcriptional coactivator 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. Glucocorticoids, using a similar mechanism, are also able to switch on a number of antiinflammatory genes. An important question is why glucocorticoids switch off only inflammatory genes, as they clearly do not suppress all activated genes and are well tolerated as long-term treatments. The interactions between NF-kappaB and the glucocorticoid receptor result in differing effects on histone acetylation and deacetylation. Oxidative stress due to cigarette smoke may be an important factor in inducing glucocorticoid resistance in chronic obstructive pulmonary disease and may involve changes in histone acetylation/deacetylation balance.
Adcock
Ian M
IM
Department of Thoracic Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, UK. ian.adcock@ic.ac.uk
Ito
Kaz
K
Barnes
Peter J
PJ
D000107:Acetylation / Q000187:drug effects; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics; D018384:Oxidative Stress / Q000502:physiology; D012307:Risk Factors; D012680:Sensitivity and Specificity; D014158:Transcription, Genetic
D005938:Glucocorticoids; D006655:Histone Deacetylases