NF-kappaB transcription factor p50 critically regulates tissue factor in deep vein thrombosis.
NF-kappaB 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-kappaB 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-kappaB 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.
Li
Yi-Dan
YD
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Graduate School of Chinese Academy of Sciences, CAS, Shanghai 200031, China.
Ye
Bu-Qing
BQ
Zheng
Sheng-Xi
SX
Wang
Jin-Tao
JT
Wang
Jian-Guo
JG
Chen
Ming
M
Liu
Ji-Guo
JG
Pei
Xin-Hui
XH
Wang
Li-Jing
LJ
Lin
Zhi-Xin
ZX
Gupta
Kalpna
K
Mackman
Nigel
N
Slungaard
Arne
A
Key
Nigel S
NS
Geng
Jian-Guo
JG
D000818:Animals; D002478:Cells, Cultured; D004224:Diterpenes / Q000494:pharmacology / Q000627:therapeutic use; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D013925:Thromboplastin / Q000096:biosynthesis*; D020246:Venous Thrombosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control
D004224:Diterpenes; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D010975:Platelet Aggregation Inhibitors; C073701:Nfkb1 protein, mouse; C030419:andrographolide; D013925:Thromboplastin