UROKINASE AND TYPE-I PLASMINOGEN-ACTIVATOR INHIBITOR PRODUCTION BY NORMAL HUMAN HEPATOCYTES - MODULATION BY INFLAMMATORY AGENTS

We examined the effects of inflammatory cytokines (interleukin-1 beta, tumor necrosis factor-alpha and transforming growth factor-beta) on t he plasminogen activator system (urokinase, tissue-type plasminogen ac tivator, type 1 plasminogen activator inhibitor) in primary cultures o f human hepatocytes. We show that interleukin-1 beta and tumor necrosi s factor-alpha increase urokinase-type plasminogen activator productio n, reinforcing the concept that increased urokinase production is asso ciated with inflammatory processes. By contrast, the same agents (i.e. , interleukin-1 beta and tumor necrosis factor-alpha) do not stimulate plasminogen activator inhibitor type 1 production. This latter observ ation rules out hepatocytes as a major cellular source of plasmatic pl asminogen activator inhibitor type 1 during acute-phase-related respon ses. Among the inflammatory agents used, transforming growth factor-be ta was found to be the most effective modulator of both urokinase-type plasminogen activator and plasminogen activator inhibitor type 1, ind ucing severalfold increases of activity of urokinase-type plasminogen activator, antigen and the corresponding mRNA and increasing plasminog en activator inhibitor type 1 antigen and mRNA levels. Urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 modul ation by transforming growth factor-beta may play a critical role in h epatic pathophysiology.