High-mobility group box 1 protein induces tissue factor expression in vascular endothelial cells via activation of NF-κB 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 HMGB I has been found in atherosclerotic plaques, its potential role in the pathogenesis of atherothrombosis remains elusive. In the present study, we determined whether HMGB I induces tissue factor (TF) expression in vascular endothelial cells (ECs) and macrophages. Our data showed that HMGB I 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, HMGB I increased expression of Egr-1 and nuclear translocation of NF-kappa B (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-kappa B and Egr-1).