++
++
Glucocorticoids (GCs) are a mainstay of dermatologic therapy because of their potent immunosuppressive and anti-inflammatory properties. In 1949, Hench and coworkers1 described the beneficial effects of cortisone in patients with rheumatoid arthritis. By understanding the properties and mechanisms of action of glucocorticoids, one can maximize their efficacy and safety as therapeutic agents.
++
The major naturally occurring glucocorticoid is cortisol (hydrocortisone). It is synthesized from cholesterol by the adrenal cortex. Normally, less than 5% of circulating cortisol is unbound; this free cortisol is the active therapeutic molecule. The remainder is inactive because it is bound to cortisol-binding globulin (CBG, also called transcortin) or to albumin. The daily secretion of cortisol ranges between 10 and 20 mg, with a diurnal peak around 8:00 am.2 Cortisol has a plasma half-life of 90 minutes. It is metabolized primarily by the liver, although it exerts hormonal effects on virtually every tissue in the body. The metabolites are excreted by the kidney and the liver.
++
The mechanism of glucocorticoid action involves passive diffusion of the glucocorticoids through the cell membrane, followed by binding to soluble receptor proteins in the cytoplasm.3 This hormone-receptor complex then moves to the nucleus and regulates the transcription of a limited number of target genes. There are three main mechanisms of glucocorticoid action. The first is direct effects on gene expression by the binding of glucocorticoid receptors to glucocorticoid-responsive elements, leading to the induction of proteins like annexin I and MAPK phosphatase 1. Annexins reduce phospholipase A2 activity, which reduces the release of arachidonic acid from membrane phospholipids,4 limiting the formation of prostaglandins and leukotrienes.5,6 The second mechanism is indirect effects on gene expression through the interactions of glucocorticoid receptors with other transcription factors. Some of the most important appear to be inhibitory effects on the transcription factors AP-1 and NF-κB, coupled with increased IκB, an inhibitor of NF-κB,7 This decreases the synthesis of a number of proinflammatory molecules, including cytokines, interleukins, adhesion molecules, and proteases. The third is glucocorticoid-receptor-mediated effects on second messenger cascades through nongenomic pathways such as the PI3K-Akt-eNOS pathway.8,9
++
The human GC receptor (GR) messenger RNA has alternative splice variants, glucocorticoid receptor–α and –β. The relative levels of these two variants influence the cell's sensitivity to glucocorticoid, with higher levels of GR-β being one of many mechanisms leading to glucocorticoid resistance.9,10
++