Mechanism of action and resistance to glucocorticoid and selective glucocorticoid receptor modulator to overcome glucocorticoid-related adverse effects

Glucocorticoids are lipid substances synthesized by the adrenal cortex that are essential for life and regulate myriad physiological processes ubiquitously in organs and tissues as mediated by intracellular glucocorticoid receptors (GRs). From the clinical standpoint, although glucocorticoids have potent anti-inflammatory and immunosuppressive effects, their adverse effects profiles and so-called glucocorticoid resistance are barriers to their widespread use. GRβ, a splice variant isoform of GRα, the predominant isoform of the receptor, and co-activators and co-repressors are believed to be important for GR-mediated actions. The mechanism of action of GRα and its co-activators and co-repressors and the mechanism of resistance to glucocorticoid treatment were investigated by confocal microscopic imaging of GRα and GRβ and by assessing protein–protein interaction of GRα and nuclear factor-κB and of GRα and activator protein-1 (AP-1). The possibility of new drug development of selective GR modulators, which reduce GR-related adverse effects such as steroid-induced osteoporosis, steroid-induced diabetes mellitus, and infection yet confer beneficial anti-inflammatory effects and immunosuppressive action is discussed.