TNF-alpha mediated suppression of tissue type plasminogen activator expression in vascular endothelial cells is NF-kappaB- and p38 MAPK-dependent.
J Thromb Haemost
; 4(8): 1781-9, 2006 Aug.
Article
en En
| MEDLINE
| ID: mdl-16879221
ABSTRACT
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.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Endotelio Vascular
/
Regulación de la Expresión Génica
/
FN-kappa B
/
Factor de Necrosis Tumoral alfa
/
Activador de Tejido Plasminógeno
/
Proteínas Quinasas p38 Activadas por Mitógenos
Límite:
Humans
Idioma:
En
Revista:
J Thromb Haemost
Asunto de la revista:
HEMATOLOGIA
Año:
2006
Tipo del documento:
Article
País de afiliación:
Suecia