DIFFERENTIAL-EFFECTS OF PHORBOL-MYRISTATE ACETATE AND DEXAMETHASONE ON PROTEIN-KINASE-C ACTIVITY AND EICOSANOIDS PRODUCTION IN CULTURED RAT ASTROCYTES

The effects of phorbol myristate acetate (PMA) and dexamethasone on protein kinase C (PK-C) activity and eicosanoid production were characterized in primary cultures of rat glial cells. PMA (1,000 ng/ml) treatment for 2 hr resulted in a maximal effect (a 4-fold increase in PGE2 Production). Longer exposure to PMA (up to 96 hr) resulted in attenuation of PGE2 production. Down-regulation of PK-C activity was assessed in glial cell homogenates under these conditions. Although a 70% inhibition of PK-C activity was measured upon staurosporine treatment, PGE2 production was not affected both under basal conditions and following PMA activation. The production of thromboxane B2 did not change following exposure to PMA. Pretreatment of the cultures with dexamethasone markedly inhibited the PMA-stimulated production of PGE2 but had only a moderate (approximately 26%) inhibitory effect on PGE2 production under basal conditions. Dexamethasone had no effect on basal or PMA-stimulated PK-C activity. Forskolin, which activates adenylate cyclase, did not affect PGE2 production. These data may suggest that activation of PGE2 production by PMA in glial cells is not unequivocally mediated by PK-C activation. The inhibitory effect of dexamethasone on the PMA-stimulated synthesis of PGE2 supports previous findings that glucocorticoids are more effective in inhibiting stimulated rather than basal PGE2 production.