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Differential mechanisms of plasminogen activator inhibitor-1 gene activation by transforming growth factor-beta and tumor necrosis factor-alpha in endothelial cells.
Thromb Haemost. 2001 Dec; 86(6):1563-72.TH

Abstract

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-beta (TGF-beta) was efficient in inducing PAI-1 promoter activation. Tissue necrosis factor-alpha (TNF-alpha) 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-alpha was due to deficient signaling pathways. BAECs responded to TNF-alpha with robust NFkappaB promoter activation. TGF-beta activated the p38 MAP kinase, while TNF-alpha activated both the SAPK/JNK and p38 MAP kinases. The ERK1/2 MAP kinases were constitutively activated in BAECs. BAEC therefore responded to TNF-alpha stimulation with activation of the MAP kinases and the NFkappaB transcriptional factors. We further measured the messenger RNA stability under the influence by TGF-beta and TNF-alpha and found no difference. PAI-1 gene activation by TNF-alpha apparently is yet to be defined for the location of the response element and/or the signaling pathway, while TGF-beta is the most important cytokine for PAI-1 transcriptional activation through its 5' proximal promoter.

Authors+Show Affiliations

Department of Cardiovascular Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

11776328

Citation

Chen, Y Q., et al. "Differential Mechanisms of Plasminogen Activator Inhibitor-1 Gene Activation By Transforming Growth Factor-beta and Tumor Necrosis Factor-alpha in Endothelial Cells." Thrombosis and Haemostasis, vol. 86, no. 6, 2001, pp. 1563-72.
Chen YQ, Sloan-Lancaster J, Berg DT, et al. Differential mechanisms of plasminogen activator inhibitor-1 gene activation by transforming growth factor-beta and tumor necrosis factor-alpha in endothelial cells. Thromb Haemost. 2001;86(6):1563-72.
Chen, Y. Q., Sloan-Lancaster, J., Berg, D. T., Richardson, M. A., Grinnell, B., & Tseng-Crank, J. (2001). Differential mechanisms of plasminogen activator inhibitor-1 gene activation by transforming growth factor-beta and tumor necrosis factor-alpha in endothelial cells. Thrombosis and Haemostasis, 86(6), 1563-72.
Chen YQ, et al. Differential Mechanisms of Plasminogen Activator Inhibitor-1 Gene Activation By Transforming Growth Factor-beta and Tumor Necrosis Factor-alpha in Endothelial Cells. Thromb Haemost. 2001;86(6):1563-72. PubMed PMID: 11776328.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential mechanisms of plasminogen activator inhibitor-1 gene activation by transforming growth factor-beta and tumor necrosis factor-alpha in endothelial cells. AU - Chen,Y Q, AU - Sloan-Lancaster,J, AU - Berg,D T, AU - Richardson,M A, AU - Grinnell,B, AU - Tseng-Crank,J, PY - 2002/1/5/pubmed PY - 2002/7/13/medline PY - 2002/1/5/entrez SP - 1563 EP - 72 JF - Thrombosis and haemostasis JO - Thromb Haemost VL - 86 IS - 6 N2 - 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-beta (TGF-beta) was efficient in inducing PAI-1 promoter activation. Tissue necrosis factor-alpha (TNF-alpha) 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-alpha was due to deficient signaling pathways. BAECs responded to TNF-alpha with robust NFkappaB promoter activation. TGF-beta activated the p38 MAP kinase, while TNF-alpha activated both the SAPK/JNK and p38 MAP kinases. The ERK1/2 MAP kinases were constitutively activated in BAECs. BAEC therefore responded to TNF-alpha stimulation with activation of the MAP kinases and the NFkappaB transcriptional factors. We further measured the messenger RNA stability under the influence by TGF-beta and TNF-alpha and found no difference. PAI-1 gene activation by TNF-alpha apparently is yet to be defined for the location of the response element and/or the signaling pathway, while TGF-beta is the most important cytokine for PAI-1 transcriptional activation through its 5' proximal promoter. SN - 0340-6245 UR - https://www.unboundmedicine.com/medline/citation/11776328/Differential_mechanisms_of_plasminogen_activator_inhibitor_1_gene_activation_by_transforming_growth_factor_beta_and_tumor_necrosis_factor_alpha_in_endothelial_cells_ L2 - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=linkout&SEARCH=11776328.ui DB - PRIME DP - Unbound Medicine ER -