1 Ann. N.Y. Acad. Sci. 1024: 1–8 (2004). © 2004 New York Academy of Sciences. doi: 10.1196/annals.1321.001 Glucocorticoids and Their Actions An Introduction EVANGELIA CHARMANDARI, TOMOSHIGE KINO, AND GEORGE P. CHROUSOS Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1583, USA KEYWORDS: glucocorticoid receptor (GR); immune response; HPA axis Glucocorticoids regulate a variety of growth, metabolic, developmental, and im- mune functions and play a pivotal role in preserving basal and stress-related homeo- stasis. 1–3 They also represent one of the most widely prescribed drugs worldwide. During the last 50 years, pharmacologic doses of glucocorticoids have been used in the treatment of inflammatory, autoimmune, and lymphoproliferative diseases, and in the prevention of graft rejection, while substitution doses have been employed in the management of adrenocortical insufficiency states. 1–3 Glucocorticoids exert their effects through the glucocorticoid receptor (GR), which belongs to the superfamily of nuclear receptors that function as ligand-dependent tran- scription factors. 4,5 Alternative splicing of the human (h) GR in exon 9 generates two highly homologous receptor isoforms, hGRα and hGRβ, which are identical through amino acid 727, but differ at their carboxyl-termini. hGRα is ubiquitously expressed in almost all human tissues and cells and represents the classic GR that functions as a ligand-dependent transcription factor, whereas hGRβ does not bind glucocorti- coids and inhibits the transcriptional activity of hGRα in a dose-dependent manner. 6–8 In the absence of ligand, hGRα resides mostly in the cytoplasm of cells as part of a large multiprotein complex, which consists of the receptor polypeptide, two mol- ecules of heat-shock protein (hsp)-90, and several other proteins. Upon ligand bind- ing, hGRα dissociates from the hsps and translocates into the nucleus of cells, where it modulates the transcriptional activity of glucocorticoid-responsive genes in either of two ways: by binding to specific sequences in the promoter region of target genes, the glucocorticoid-response elements (GREs), or through protein–protein interac- tions with other transcription factors, such as nuclear factor (NF)-κB, activator pro- tein-1 (AP-1), and several signal transducers and activators of transcription (STATs). 9–11 Newly characterized nuclear receptor coregulators (coactivators or corepressors) may also enhance or attenuate glucocorticoid signal transduction Address for correspondence: Evangelia Charmandari, M.D., National Institutes of Health, Building 10, Room 9D42, 10 Center Drive MSC 1583, Bethesda, MD 20892-1583. Voice: 301- 496-5800; fax: 301-402-0884. charmane@mail.nih.gov