NF-κB transcription factor p50 critically regulates tissue factor in deep vein thrombosis

Yi Dan Li, Bu Qing Ye, Sheng Xi Zheng, Jin Tao Wang, Jian Guo Wang, Ming Chen, Ji Guo Liu, Xin Hui Pei, Li Jing Wang, Zhi Lin Lin, Kalpna Gupta, Nigel Mackman, Arne Slungaard, Nigel S. Key, Jian Guo Geng

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62 Scopus citations

Abstract

NF-ΚB transcription factors regulate the expression of tissue factor (TF), a principal initiator of the coagulation cascade. Dominant among them is the p50/p65 heterodimer. Here we report that Andrographolide (Andro; a p50 inhibitor) and genetic deletion of p50 attenuated TF activity in stimulated endothelial cells and monocytes/ macrophages. Results of the electrophoretic mobility "supershift" assay and chromatin immunoprecipitation demonstrated the direct interaction of the p50/p65 heterodimer with the NF-κB site of the human TF promoter. Andro-treated and p50 null mice both exhibited blunted TF expression and reduced venous thrombosis, which were recapitulated by an anti-murine TF antibody in vivo. Our findings thus indicate that regulation of TF by NF-κB transcription factor p50 is essential for the pathogenesis of deep vein thrombosis and suggest that specific inhibitors of p50, such as Andro, may be therapeutically valuable for preventing and perhaps treating venous thrombosis.

Original languageEnglish (US)
Pages (from-to)4473-4483
Number of pages11
JournalJournal of Biological Chemistry
Volume284
Issue number7
DOIs
StatePublished - Feb 13 2009

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