Glucocorticoid signaling: a nongenomic mechanism for T-cell immunosuppression.
Glucocorticoids were long believed to exert their effects through transcriptional regulation of glucocorticoid-receptor target genes. However, there is accumulating evidence for nongenomic glucocorticoid-receptor-dependent modulation of signal transduction pathways. Here, we review rapid glucocorticoid activities and focus on a novel mechanism that underlies nongenomic glucocorticoid-induced immunosuppression in T cells. The findings demonstrate a physical and functional interaction between the glucocorticoid receptor and the T-cell receptor (TCR) complex. In its unligated state, the glucocorticoid receptor has an important role in TCR signaling but, after glucocorticoid-receptor-ligand binding (caused by short-term treatment with the synthetic glucocorticoid dexamethasone), the TCR complex is disrupted, leading to impaired TCR signaling. These data reveal a dichotomal functional role for glucocorticoid receptors: one in the cytosol as part of the TCR complex and the other as a nuclear regulator of gene transcription. Drugs that selectively target membrane-bound glucocorticoid receptors might represent a novel immunosuppressive approach.
Löwenberg
Mark
M
Department of Gastroenterology and Hepatology, Academic Medical Center, Meibergdreef, Amsterdam, The Netherlands. m.lowenberg@amc.uva.nl
Verhaar
Auke P
AP
van den Brink
Gijs R
GR
Hommes
Daniel W
DW
D000818:Animals; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D008954:Models, Biological; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D011987:Receptors, Steroid / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism
D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D011948:Receptors, Antigen, T-Cell; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid