Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-alpha, and transforming growth factor-beta.
The regulation of type 1 plasminogen activator inhibitor (PAI-1) gene expression was studied in vivo employing a murine model system. Nuclease protection analysis revealed relatively high concentrations of PAI-1 mRNA in the aorta, adipose tissue, heart, and lungs of untreated CB6 (BalbC X C57B16) mice. Treatment of CB6 mice with LPS, TNF-alpha, or transforming growth factor-beta (TGF-beta) increased the steady-state levels of PAI-1 mRNA within 3 h in all tissues examined. However, the greatest responses to TGF-beta were observed in adipose tissue and the kidney, while LPS and TNF-alpha strongly stimulated PAI-1 gene expression in the liver, kidney, lung, and adrenals. In C3H/HeJ mice, which exhibit defective TNF-alpha release in response to LPS, the response of the PAI-1 gene to LPS was severely attenuated. However, injection of these mice with TNF-alpha increased PAI-1 mRNA in a tissue-specific pattern strikingly similar to that observed in LPS-treated CB6 mice. These results demonstrate that the PAI-1 gene is regulated in a complex and tissue-specific manner in vivo, and suggest a role for TNF-alpha in the response of the PAI-1 gene to sepsis.
Committee on Vascular Biology, Research Institute of Scripps Clinic, La Jolla, California 92037.
M S
MS
Sawdey
D J
DJ
Loskutoff
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D015849:Plasminogen Inactivators; D012333:RNA, Messenger / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D008070:Lipopolysaccharides; D015849:Plasminogen Inactivators; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha