INDUCTION OF PLASMINOGEN-ACTIVATOR INHIBITOR-1 GENE-EXPRESSION IN MURINE LIVER BY LIPOPOLYSACCHARIDE - CELLULAR-LOCALIZATION AND ROLE OF ENDOGENOUS TUMOR-NECROSIS-FACTOR-ALPHA

We previously demonstrated that lipopolysac-charide (LPS) induces Plas minogen activator inhibitor 1 (PAI-1) gene expression primarily in end othelial cells in most organs of the mouse, with maximal induction by 3 hours. Here we show that induction in the liver occurs in a distinct ly different pattern. For example, the increase in PAI-1 mRNA in liver was biphasic with an initial peak at 1 to 2 hours and a second peak a t 6 to 8 hours. Moreover in situ hybridization experiments revealed th at PAI-1 mRNA was induced its both endothelial cells and hepatocytes. The endothelial cell response was monophasic and maximal between 1 and 4 hours, whereas the hepatocyte response was biphasic, peaking at 2 h ours and again at 6 to 8 hours. To determine Possible mechanisms invol ved ill the induction of PAl-1 by LPS, we analyzed the tissues for cha nges in tumor necrosis factor (TNF)-alpha. LPS caused a rapid inductio n of TNF-alpha mRNA in Kupffer cells, detectable within 15 minutes. Pr etreatment of mice with anti-TNF antiserum before challenge with LPS r educed the subsequent increase in Plasma levels of PAI-1 by 50 to 70% and significantly reduced the level of induction of PAI-1 mRNA in the liver at both early and late times Pretreatment appeared to inhibit in duction Primarily within hepatocytes, These results suggest that LPS m ay induce PAI-I in endothelial cells and hepatocytes by different mech anisms.