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Thromb Haemost 2001; 86(06): 1563-1572
DOI: 10.1055/s-0037-1616763
Review Article
Schattauer GmbH

Differential Mechanisms of Plasminogen Activator Inhibitor-1 Gene Activation by Transforming Growth Factor-β and Tumor Necrosis Factor-α in Endothelial Cells

Yan Q. Chen
1   Departments of Cardiovascular Research
,
Joanne Sloan-Lancaster
2   Bio Research Technology and Proteins, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
,
David T. Berg
2   Bio Research Technology and Proteins, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
,
Mark A. Richardson
2   Bio Research Technology and Proteins, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
,
Brian Grinnell
2   Bio Research Technology and Proteins, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
,
Julie Tseng-Crank
1   Departments of Cardiovascular Research
› Author Affiliations
Further Information

Publication History

Received 12 December 2000

Accepted 12 July 2001

Publication Date:
12 December 2017 (online)

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Summary

Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor (SERPIN) specific for tissue-type and urokinase-like plasminogen activators. High plasma PAI-1 activity is a risk factor for thrombotic diseases. Due to the short half-life of PAI-1, regulation of PAI-1 gene expression and secretion of active PAI-1 into the blood stream is important for hemostatic balance. We have investigated transcriptional control of PAI-1 gene expression in bovine aortic endothelial cells (BAECs) and human cell lines using PAI-1 5’ promoter-luciferase reporter assays. Contrary to the cytokine-induced up-regulation of PAI-1 mRNA and protein levels, we found that only transforming growth factor-β (TGF-β) was efficient in inducing PAI-1 promoter activation. Tissue necrosis factor-α (TNF-α) induced a small luciferase activity with the 2.5 kb PAI-1 promoter, but not with the PAI-800/4G/5G and p3TP-lux promoters. Next we investigated whether a lack of response to TNF-α was due to deficient signaling pathways. BAECs responded to TNF-α with robust NFκB promoter activation. TGF-β activated the p38 MAP kinase, while TNF-α activated both the SAPK/JNK and p38 MAP kinases. The ERK1/2 MAP kinases were constitutively activated in BAECs. BAEC therefore responded to TNF-α stimulation with activation of the MAP kinases and the NFκB transcriptional factors. We further measured the messenger RNA stability under the influence by TGF-β and TNF-α and found no difference. PAI-1 gene activation by TNF-α apparently is yet to be defined for the location of the response element and/or the signaling pathway, while TGF-β is the most important cytokine for PAI-1 transcriptional activation through its 5’ proximal promoter.

Keywords

Plasminogen activator inhibitor-1 - transforming growth factor-β - tumor necrosis factor-α - MAP kinase - endothelium
 

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