Thrombin regulation of tissue-type plasminogen activator synthesis in cultured human fetal lung fibroblasts

We examined the effects of thrombin on tissue-type plasminogen activator (t-PA) release and t-PA mRNA levels in cultured human fetal lung fibroblast cells, IMR-90. The secretion of t-PA was increased by thrombin in a dose- and time-dependent manner, but it was not affected by inactivated thrombin with diisopropylfluorophosphate (DFP). Both antithrombin III (ATIII) and heparin cofactor II (HCII), plasma inhibitors to thrombin, inhibited thrombin-induced t-PA release. The thrombin-induced t-PA secretion was preceded by an increase of the steady state level of t-PA-specific mRNA in the cells, suggesting that thrombin activates t-PA gene expression. The t-PA mRNA expression induced by thrombin was completely blocked by pretreatment of the cells with an inhibitor of translation, cycloheximide (CHX). These results suggest that the effect of thrombin on t-PA expression is mediated through its proteolytic activity and the biosynthesis of transcription factor(s).