Paradoxical effects of glucocorticoids on regulation of plasminogen activator activity of rat hepatoma cells.

Incubation of rat hepatoma cells with cAMP derivatives stimulates cell-associated plasminogen activator activity 8- to 22-fold and extracellular plasminogen activator activity 30- to 1300-fold. This time- and concentration-dependent increase is enhanced by phosphodiesterase inhibitors. Dexamethasone, a synthetic glucocorticoid, decreases the plasminogen activator activity of these cells, probably through induction of an inhibitor. Paradoxically, dexamethasone, added simultaneously with cAMP derivatives causes a further 4-fold enhancement of the cAMP-mediated stimulation of plasminogen activator activity. Dexamethasone also alters the time course of cAMP-mediated enhancement of plasminogen activator activity: increased protease activity is detected at 4 hr in cells incubated with 8-bromoadenosine-3':5'-cyclic monophosphoric acid and 1-methyl-3-isobutylxanthine but not until 12 hr in cells incubated with dexamethasone as well. Glucocorticoids thus exert two separate and opposite effects on plasminogen activator activity: induction of an inhibitor and amplification of cyclic nucleotide action. Although permissive and synergistic effects of dexamethasone on cyclic nucleotide action have been reported previously, glucocorticoid regulation of plasminogen activator activity is unique in that the amplification of cyclic nucleotide effects by dexamethasone opposes its regulatory action toward a specific enzyme.