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 lipopolysaccharide (LPS) induces plasminogen activator inhibitor 1 (PAI-1) gene expression primarily in endothelial cells in most organs of the mouse, with maximal induction by 3 hours. Here we show that induction in the liver occurs in a distinctly 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 at 6 to 8 hours. Moreover, in situ hybridization experiments revealed that PAI-1 mRNA was induced in 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 hours and again at 6 to 8 hours. To determine possible mechanisms involved in the induction of PAI-1 by LPS, we analyzed the tissues for changes in tumor necrosis factor (TNF)-alpha LPS caused a rapid induction of TNF-alpha mRNA in Kupffer cells, detectable within 15 minutes. Pretreatment of mice with anti-TNF antiserum before challenge with LPS reduced 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 induction primarily within hepatocytes. These results suggest that LPS may induce PAI-1 in endothelial cells and hepatocytes by different mechanisms.
Fearns
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Department of Vascular Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
Loskutoff
D J
DJ
D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha