INDUCTION OF PLASMINOGEN-ACTIVATOR INHIBITOR-1 IN HEPG2 HUMAN HEPATOMA-CELLS BY MEDIATORS OF THE ACUTE-PHASE RESPONSE

The liver plays a central role in the systemic acute phase response of an organism to injury. Plasminogen activator inhibitor-1 (PAI-1), a m ajor regulator of fibrinolysis, is an important component of the acute phase response in humans. The source of plasma PAI-1 has been a matte r of controversy, but recent in situ hybridization experiments have de monstrated that human hepatocytes express the PAI-1 gene in vivo. Howe ver, little is known about regulation of human hepatic PAI-1 gene expr ession by mediators of the acute phase response. We have analyzed the regulation of PAI-1 mRNA accumulation by interleukin (IL)-1, IL-6, and dexamethasone, known mediators of the acute phase response, in HepG2 cells, a highly differentiated human hepatoma cell line that produces a broad spectrum of acute phase proteins including PAI-1. Incubation o f HepG2 cells with IL-1 resulted in a rapid and transient 40-fold indu ction of the 3.2-kilobase PAI-1 mRNA and a 30-fold induction of the 2. 2-kilobase PAI-1 mRNA Although IL-6 alone had only a modest effect on PAI-1 expression, in combination with IL-1, it caused a synergistic in duction of PAI-1 mRNA accumulation. Dexamethasone alone did not increa se PAI-1 mRNA accumulation but enhanced it in combination with IL-1. U sing nuclear run-on experiments, we determined that the mechanism by w hich IL-1 alone, or in combination with IL-6, induced PAI-1 mRMA accum ulation was to cause a 10-15-fold, transient stimulation of PAI-1 gene transcription. We found no evidence of an effect of these cytokines o n PAI-1 mRNA stability. These data demonstrate that mediators of the a cute phase response induce the accumulation of PAI-1 mRNA in human hep atoma cells by rapidly and transiently increasing the transcription of the PAI-1 gene.