[Mode of action of glucocorticoids]

RECEPTORS: The effect of glucocorticoids is mediated by a receptor mainly found in the cytoplasm. The glucocorticoid receptor is a member of the nuclear receptor superfamily. RECEPTOR ACTIVATION: When unstimulated, the glucocorticoid receptor is inactivated by its integration within a multiple-protein complex associating heat shock proteins, immunophilins and cyclophilins. When the hormone binds to its receptor, the complex dissociates and the receptor migrates to the nucleus. In the nucleus, the activated receptor provokes an upregulation or downregulation of target gene expression. GENE REGULATION: Gene expression may be regulated via an interaction between specific nucleic acid sequences of the glucocorticoid receptor and nuclear DNA (direct mechanism) or by protein-protein interactions (indirect mechanism). The expression of target genes is either inhibited or stimulated. PHARMACOLOGICAL CONSEQUENCES: The main pharmacological applications of glucocorticoids can be explained by these different mechanisms. The antiinflammatory action of glucocorticoids results from an inhibition of the transcription of the collagenase gene via an interaction with the AP-1 transcription factor. The anticancer action of glucocorticoids results from the induction of apoptotic cell death via a mechanism which would require the transcriptional activity of the glucocorticoid receptor.