Glucocorticoid Receptor Signaling

Glucocorticoids (GCs), a major subclass of steroid hormones, regulate a large number of immune, metabolic, cardiovascular and behavioral functions. GCs are produced and released from the adrenal cortex under the control of the hypothalamic-pituitary-adrenal axis.Glucocorticoids produce their effect on responsive cells by activating the glucocorticoid receptor (GR) to directly or indirectly modulate the transcription of target genes.Because of their lipophilic nature and low molecular weight, GCs passively diffuse across the lipid bilayer of the cell membrane into the cytoplasm where they bind the intracellular GR.In the absence of glucocorticoids, GR is present in the cytoplasm as an inactive complex with HSP-90 and other chaperone proteins. Upon binding to glucocorticoids, GR undergoes conformational changes, dissociates from HSP-90, and subsequently translocates to the nucleus, where it binds as a homodimer to GC-response elements (GRE) and to negative GRE (nGRE) in the promoter of positively and negatively regulated genes, respectively.In spite of the ability of glucocorticoids to induce anti-inflammatory gene transcription, the major anti-inflammatory effects of glucocorticoids are through repression of inflammatory genes. The inhibitiory effect of GCs is mediated in part through a GRE-independent mechanism. Monomeric GR can repress transcription of cytokine genes through direct interaction and inhibition of the nuclear transcription factors AP-1, NF-κB and NF-AT.These anti-inflammatory actions are also complemented by the ability of glucocorticoids to induce apoptosis of cells including monocytes and T lymphocytes. (Upgraded 07/2020)