Mechanisms of glucocorticoid receptor action

Glucocorticoids (GC) cross freely into the cytoplasm where they bind to and activate the glucocorticoid receptor (GR). Activated GR translocates into the nucleus where it can bind as a dimer to a glucocorticoid response element (GRE) and induce the expression of anti-inflammatory genes such as the IL-10 gene. This involves a change in local histone acetylation status and chromatin remodeling. Secondly, the GR dimer can bind to a negative GRE to prevent inflammatory gene expression preventing formation of an active transcriptional complex. Thirdly, GR, acting as a monomer, binds directly or indirectly with pro-inflammatory transcription factors such as nuclear factor kappaB (NF-kappaB) preventing its ability to switch on inflammatory gene expression. The increased expression of the GRbeta isoform found in some patients with glucocorticoid insensitive severe asthma can act as a dominant negative regulator of GRalpha.