High-mobility group box 1 protein induces tissue factor expression in vascular endothelial cells via activation of NF-kappaB and Egr-1.
High-mobility group box 1 protein (HMGB1), an abundant nuclear protein, was recently established as a proinflammatory mediator of experimental sepsis. Although extracellular HMGB1 has been found in atherosclerotic plaques, its potential role in the pathogenesis of atherothrombosis remains elusive. In the present study, we determined whether HMGB1 induces tissue factor (TF) expression in vascular endothelial cells (ECs) and macrophages. Our data showed that HMGB1 stimulated ECs to express TF (but not TF pathway inhibitor) mRNA and protein in a concentration- and time-dependent manner. Blockade of cell surface receptors (including TLR4, TLR2, and RAGE) with specific neutralising antibodies partially reduced HMGB1-induced TF expression. Moreover, HMGB1 increased expression of Egr-1 and nuclear translocation of NF-kappaB (c-Rel/p65) in ECs. Taken together, our data suggest that HMGB1 induces TF expression in vascular endothelial cells via cell surface receptors (TLR4, TLR2, and RAGE), and through activation of transcription factors (NF-kappaB and Egr-1).
Lv
Ben
B
Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, People's Republic of China.
Wang
Haichao
H
Tang
Yiting
Y
Fan
Zhang
Z
Xiao
Xianzhong
X
Chen
Fangping
F
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D024243:HMGB1 Protein / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013925:Thromboplastin / Q000096:biosynthesis* / Q000235:genetics*; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D024243:HMGB1 Protein; D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011994:Recombinant Proteins; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D013925:Thromboplastin