Molecular mechanisms of corticosteroid actions.

Corticosteroids are the most effective therapy for the treatment of inflammatory diseases such as asthma. Functionally, they act partly by inducing anti-inflammatory genes such as secretary leukocyte proteinase inhibitor, Lipocortin-1 and interleukin-1 receptor antagonist, but mainly by repression of inflammatory genes, such as cytokines, adhesion molecules, inflammatory enzymes and receptors. They act by binding to a cytosolic glucocorticoid receptor (GR), which upon binding is activated and rapidly translocates to the nucleus. Within the nucleus, the GR either induces gene transcription by binding to specific deoxyribonucleic acid elements in the promoter/enhancer regions of responsive genes or reduces gene transcription by transrepression. The GR reduces gene transcription by interaction with pro-inflammatory transcription factors such as activation protein-1 and nuclear factor-kappa B. These effects of the GR on gene expression involve changes in the chromatin structure localized to the promoter sites of responsive genes. Many of the detrimental side-effects of corticosteroids are believed to be due to gene induction, leading to the search for novel corticosteroids which can repress inflammatory genes without inducing gene transcription.