Studies on biomodulators of glucocorticoid action: amplifiers and suppressors of glucocorticoid action.

In this work we found that the induction of tyrosine aminotransferase by glucocorticoid in rat hepatocytes was suppressed concentration-dependently by TGF-beta and H-7, an inhibitor of protein kinase C, but not by other polypeptide growth factors tested or by H-8, an inhibitor of cyclic nucleotide dependent protein kinases. EGF, on the contrary, amplified the induction in the same way as activators of protein kinase C, such as 12-o-tetradecanoyl-phorbol 13-acetate (2,3) and 1,2-racemic dioctanoyl glycerol (1,3). These findings indicate that TGF-beta and H-7 act in the suppressive direction and EGF acts in the enhance direction on the action of glucocorticoid. H-7 inhibited the accumulation of glucocorticoid-receptor complexes in the nuclear fraction with associated accumulation of these complexes in the cytoplasmic fraction, but did not affect incorporation of glucocorticoid into hepatocytes. These results suggest that protein kinase C is essential in translocation of glucocorticoid-receptor complexes to the nuclei and that its inhibitors suppress glucocorticoid actions.