Molecular Mechanisms of Glucocorticoid Receptor Action

Glucocorticoids are the most effective therapy for the treatment of many chronic infl ammatory diseases such as asthma and infl ammatory bowel disease (Ito et al., 2006a). In contrast to the situation in asthma, chronic obstructive pulmonary disease (COPD), a common and debilitating chronic infl ammatory disease of the lung, is glucocorticoid insensitive (Barnes, 2000a, b; Culpitt et al., 2003). Glucocorticoids act by binding to cytosolic glucocorticoid receptors (GRs), which upon binding become activated and rapidly translocate to the nucleus. Within the nucleus, GR either induces transcription of genes such as secretary leukocyte proteinase inhibitor (SLPI)(Abbinante-Nissen et al., 1995) and mitogen-activated kinase phosphatase-1(Lasa et al., 2002) by binding to specifi c DNA elements (glucocorticoid response element, GRE) at the promoter/enhancer of responsive genes, or reduces infl ammatory gene transcription induced by nuclear factor-kappa B (NF-κB) or other pro-infl ammatory transcription factors (Ito et al., 2006a). Binding of GR to p65-NFκB is crucial for transrepression by glucocorticoids, however, it is not clear how the GR dissociates its ability to control infl ammation by suppressing NF-κB from its ability to directly transactivate genes via binding to GRE (Ito et al., 2006b). In the resting cell, chromatin is tightly compacted to prevent transcription factor accessibility. During activation of the cell this compact inaccessible chromatin is made available to DNA-binding proteins, thus allowing the induction of gene transcription (Lee and Workman, 2007; Li et al., 2007). There is compelling evidence that increased infl ammatory gene transcription is associated with an increase in histone acetylation induced by transcriptional coactivators containing