Dexamethasone inhibition of tissue-type plasminogen activator (tPA) activity: paradoxical induction of both tPA antigen and plasminogen activator inhibitor.
Incubation of HTC rat hepatoma cells with the synthetic glucocorticoid dexamethasone rapidly inhibits plasminogen activator (PA) activity and reveals the presence of a specific PA inhibitor (PAI-1). To determine whether the hormonal inhibition of PA activity reflects a decrease in the amount of PA or an increased amount of the inhibitor, or both, we have assayed PA and PAI-1 immunologically. HTC PA was determined to be entirely of the tissue type (tPA), and both free and complexed antigen was quantified by a RIA using rabbit antirat tPA, with rat insulinoma tPA as tracer and standard. PAI-1 was quantified by a Western blot assay using rabbit anti-HTC PAI-1 antibody and purified HTC PAI-1 as standard. Under conditions in which dexamethasone inhibited PA activity by 90%, there was no decrease in the cellular content of tPA antigen. Paradoxically, dexamethasone increased tPA antigen approximately 1.5-fold. Under these same conditions, dexamethasone increased PAI-1 antigen 4- to 5-fold. We conclude that the glucocorticoid inhibition of tPA activity in HTC cells is not secondary to a decrease in the amount of tPA but is secondary to the induction of a specific PA inhibitor.
D000818:Animals; D000941:Antigens / Q000235:genetics* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms; D008114:Liver Neoplasms, Experimental; D010960:Plasminogen Activators / Q000037:antagonists & inhibitors; D015849:Plasminogen Inactivators; D011863:Radioimmunoassay; D051381:Rats; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000941:Antigens; D005938:Glucocorticoids; D006023:Glycoproteins; D015849:Plasminogen Inactivators; D003907:Dexamethasone; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator