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.