NEW INSIGHTS INTO THE MOLECULAR BASIS OF GLUCOCORTICOID ACTION

Abstract

Because of the realization that inflammation plays a primary role in the pathogenesis of asthma, glucocorticoids are now considered to be the most efficacious antiasthmatic agents. 12 The anti-inflammatory effects of glucocorticoids are mediated through receptors that function by modulating gene expression. Glucocorticoid receptors (GRs) are members of the large steroid/nuclear receptor family that also includes receptors for mineralocorticoids, androgens, estrogens, progesterone, vitamin D, thyroid hormone, and retinoic acid. During the past decade, there has been a tremendous increase in the knowledge of the mechanisms through which glucocorticoids affect gene expression. Much is known about how glucocorticoids enhance activation of gene expression, but an important aspect of the anti-inflammatory effects of glucocorticoids in asthma involves repression of the expression of inflammatory mediators, particularly cytokines. There is less knowledge concerning the mechanisms through which glucocorticoids repress gene expression, but this is an important area of research. Studies have also recently demonstrated a significant role for steroid/nuclear receptor co-activators, histone acetylation, and chromatin structure in gene regulation. This article begins with an overview of glucocorticoid receptors and glucocorticoid-induced gene activation and then focuses on mechanisms of glucocorticoid-mediated gene repression.