TNF-α mediated suppression of tissue type plasminogen activator expression in vascular endothelial cells is NF-κB- and p38 MAPK-dependent

E. Ulfhammer, P. Larsson, L. Karlsson, T. Hrafnkelsdóttir, M. Bokarewa, A. Tarkowski, Sverker Jern

Research output: Contribution to journalArticleResearchpeer-review

33 Citations (Scopus)

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)-α 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-α the nuclear factor kappa-B (NF-κB), the p38 mitogen-activated protein kinase (p38 MAPK), and the c-jun N-terminal kinase (JNK) pathways. Following TNF-α 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-α (≥24 h). The repression was shown to be preferentially dependent on NF-κB activation, but also on p38 MAPK signaling. Further, we provide evidence for a TNF-α induced binding of NF-κB to the recently described κB 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-α impairs fibrinolytic capacity in vascular endothelial cells by a NF-κB and p38 MAPK-dependent suppression of t-PA. This mechanism sheds a light on how inflammation contributes to the pathogenesis of cardiovascular diseases.

Original languageEnglish
Pages (from-to)1781-1789
Number of pages9
JournalJournal of Thrombosis and Haemostasis
Volume4
Issue number8
DOIs
Publication statusPublished - 1 Aug 2006
Externally publishedYes

Keywords

  • Endothelium
  • Fibrinolysis
  • Nuclear factor kappa-B
  • p38 mitogen-activated protein kinase
  • Tissue-type plasminogen activator
  • Tumor necrosis factor- α

Cite this