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TNF-alpha mediated ...
TNF-alpha mediated suppression of tissue type plasminogen activator expression in vascular endothelial cells is NF-kappaB- and p38 MAPK-dependent
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- Ulfhammer, Erik, 1974 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för akut och kardiovaskulär medicin,Institute of Medicine, Department of Emergeny and Cardiovascular Medicine
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- Larsson, Pia, 1978 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research
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- Karlsson, Lena, 1964 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för akut och kardiovaskulär medicin,Institute of Medicine, Department of Emergeny and Cardiovascular Medicine
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- Hrafnkelsdottir, Thordis, 1965 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för akut och kardiovaskulär medicin,Institute of Medicine, Department of Emergeny and Cardiovascular Medicine
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- Bokarewa, Maria, 1963 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research
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- Tarkowski, Andrej, 1951 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research
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- Jern, Sverker, 1954 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för akut och kardiovaskulär medicin,Institute of Medicine, Department of Emergeny and Cardiovascular Medicine
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(creator_code:org_t)
- 2006
- 2006
- English.
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In: J Thromb Haemost. - 1538-7933. ; 4:8, s. 1781-9
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Abstract
Subject headings
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- BACKGROUND: Several proatherothrombotic conditions are associated with enhanced levels of circulating proinflammatory cytokines, which are believed to impair endothelial fibrinolytic capacity. Objective: This study aims at investigating how tumor necrosis factor (TNF)-alpha regulates endothelial gene expression of the key fibrinolytic enzyme tissue-type plasminogen activator (t-PA). METHODS: Cultured human umbilical vein endothelial cells were pretreated with selective inhibitors of the three major inflammatory signaling pathways activated by TNF-alpha; the nuclear factor kappa-B (NF-kappaB), the p38 mitogen-activated protein kinase (p38 MAPK), and the c-jun N-terminal kinase (JNK) pathways. Following TNF-alpha stimulation, effects on t-PA gene expression were evaluated with real-time reverse transcriptase polymerase chain reaction and interactions of nuclear proteins with potential gene regulatory elements were studied with electrophoretic mobility shift assays. RESULTS: Approximately 50% suppression of t-PA gene expression was observed after prolonged stimulation with TNF-alpha (> or =24 h). The repression was shown to be preferentially dependent on NF-kappaB activation, but also on p38 MAPK signaling. Further, we provide evidence for a TNF-alpha induced binding of NF-kappaB to the recently described kappaB site in the t-PA gene and of cyclic adenosine monophosphate response element binding protein (CREB) to the t-PA CRE-like site. CONCLUSIONS: We conclude that TNF-alpha impairs fibrinolytic capacity in vascular endothelial cells by a NF-kappaB and p38 MAPK-dependent suppression of t-PA. This mechanism sheds a light on how inflammation contributes to the pathogenesis of cardiovascular diseases.
Keyword
- Binding Sites
- Cardiovascular Diseases/metabolism
- Cells
- Cultured
- Endothelium
- Vascular/cytology/*metabolism
- Fibrinolysis
- *Gene Expression Regulation
- Humans
- Inflammation
- NF-kappa B/*metabolism
- Protein Structure
- Tertiary
- Signal Transduction
- Tissue Plasminogen Activator/*biosynthesis
- Tumor Necrosis Factor-alpha/metabolism/*physiology
- Umbilical Veins/cytology
- p38 Mitogen-Activated Protein Kinases/*metabolism
Publication and Content Type
- ref (subject category)
- art (subject category)
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Ulfhammer, Erik, ...
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Larsson, Pia, 19 ...
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Karlsson, Lena, ...
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Hrafnkelsdottir, ...
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Bokarewa, Maria, ...
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Tarkowski, Andre ...
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Jern, Sverker, 1 ...
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- Articles in the publication
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J Thromb Haemost
- By the university
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University of Gothenburg