Mode of action of glucocorticoids

Receptors: The effect of glucocorticoids is mediated by a receptor mainly f ound in the cytoplasm. The glucocorticoid receptor is a member of the nucle ar receptor superfamily. Receptor activation: When unstimulated, the glucocorticoid receptor is inac tivated by its integration within a multiple-protein complex associating he at shock proteins, immunophilins and cyclophilins. When the hormone binds t o its receptor, the complex dissociates and the receptor migrates to the nu cleus. In the nucleus, the activated receptor provokes an upregulation or d ownregulation of target gene expression. Gene regulation: Gene expression may be regulated via an interaction betwee n specific nucleic acid sequences of the glucocorticoid receptor and nuclea r DNA (direct mechanism) or by protein-protein interactions (indirect mecha nism). The expression of target genes is either inhibited or stimulated. Pharmacological consequences: The main pharmacological applications of gluc ocorticoids can be explained by these different mechanisms. The antiinflamm atory action of glucocorticoids results from an inhibition of the transcrip tion of the collagenase gene via an interaction with the AP-I transcription factor. The anticancer action of glucocorticoids results from the inductio n of apoptotic cell death via a mechanism which would require the transcrip tional activity of the glucocorticoid receptor.