[Glucocorticoids and their receptor: mechanisms of action and clinical implications]

Glucocorticoids are used as anti-inflammatory, immuno-modulatory, anti-proliferative and cytotoxic drugs, but they also trigger important side-effects. These hormones bind to glucocorticoid receptor alpha (GRalpha), an intracellular protein, which acts essentially in the nucleus.

GRalpha is a ligand-activated transcription factor that positively or negatively regulates gene expression by distinct mechanisms. Stimulation of gene transcription occurs after direct binding of the receptor to specific responsive DNA elements. Gene activation by glucocorticoids is mainly responsible for certain adverse effects. In contrast, the therapeutic effects of glucocorticoids are predominantly mediated through repression of genes encoding inflammatory mediators. Inhibitory protein-protein interaction between the hormone-activated receptor and the transcription factors NF-kappaB and AP-1 was found to be the underlying mechanism. However, inhibition of other transcription factors may account for deleterious effects of glucocorticoids, such as adrenal suppression and osteoporosis. GRalpha also mediates rapid non-genomic effects of glucocorticoids. Side-effects are reduced by using topical glucocorticoids which have a low systemic bioavailability. Moreover, it is important to determine the lowest effective maintenance dose of systemic and topical glucocorticoids to further decrease the risk of adverse effects. This is particularly justified because inhibition of AP-1 and NF-kappaB activities, that is the anti-inflammatory effect, occurs at much lower hormone concentrations than transactivation.

Clinical use of glucocorticoids is limited by occurrence of severe adverse effects. Therefore, the current aim is to design GRalpha ligands that retain only the anti-inflammatory activities of GC.