Corticosteroids inhibit the delivery of short-term activational pulses of phorbol ester and calcium ionophore to human peripheral T cells.
Although there is evidence that corticosteroids inhibit receptor-ligand-induced phospholipid hydrolysis, the immunosuppressive effects of these agents downstream of protein kinase C (PK-C) activation and cytosolic Ca2+ mobilization is unclear. Previous studies indicated that T cell proliferative activation could be achieved with simultaneous short-term (e.g., 15-120 min) exposure to agents activating PK-C and elevating cytosolic Ca2+. In the studies reported here, similar procedures were utilized for determining whether corticosteroids alter T cell activation signals downstream of second messenger events. Dexamethasone interfered with T cell activation induced by short-term exposure to phorbol 12,13-dibutyrate (PDBu) and the calcium ionophore, ionomycin. The inhibitory effect was evident with as little as 15 min of exposure to dexamethasone and T cell activating agents, making mechanisms involving de novo protein synthesis unlikely. Dexamethasone's effects in this system were blocked by the steroid receptor antagonist RU-486, indicating that the inhibition was mediated through the glucocorticoid receptor. The inclusion of recombinant interleukin-2 (IL-2) only partially overcame the dexamethasone inhibitory effect. Long-term (i.e., 48 hr) direct stimulation of PK-C with either PDBu or the non-tumor-promoting PK-C activator, bryostatin 1, also substantially overcame dexamethasone's effects, resulting in a recovery of IL-2 production and significant restoration of the T-cell proliferative response. These observations suggest that treatment with a PK-C-activating agent such as bryostatin 1 could reduce glucocorticosteroid-induced immunosuppression.
McVicar
D W
DW
Department of Anatomy, Virginia Commonwealth University, Medical College of Virginia, Richmond 23298.
McCrady
C W
CW
Merchant
R E
RE
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D054713:Bryostatins; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007376:Interleukin-2 / Q000032:analysis; D015759:Ionomycin / Q000494:pharmacology*; D007783:Lactones / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D018942:Macrolides; D015735:Mifepristone / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D015290:Second Messenger Systems; D013601:T-Lymphocytes / Q000187:drug effects*; D013997:Time Factors
D000305:Adrenal Cortex Hormones; D054713:Bryostatins; D007376:Interleukin-2; D007783:Lactones; D018942:Macrolides; D015735:Mifepristone; D015240:Phorbol 12,13-Dibutyrate; C046785:bryostatin 1; D015759:Ionomycin; D003907:Dexamethasone; D011493:Protein Kinase C; D002118:Calcium