Extracellular
histones have been recognized recently as proinflammatory mediators; they are released from dying cells in response to inflammatory challenge, contributing to endothelial cell dysfunction,
thrombin formation, organ failure, and death during
sepsis. Clinical studies suggest that the plasma concentration of the
histone-
DNA complex is correlated with the severity of
DIC and is a poor independent prognostic marker in
sepsis. In addition, platelet activation stimulates
thrombus formation. Whether
histones contribute to procoagulant activity in other ways remains elusive. In this study, we confirmed that
histones induce
tissue factor (TF) expression in a concentration- and time-dependent manner in vascular endothelial cells (ECs) and macrophages. However,
histones did not affect TF pathway inhibitor expression. Moreover, blocking the
cell surface receptors TLR4 and TLR2 with specific
neutralizing antibodies significantly reduced
histone-induced TF expression. Furthermore,
histones enhanced the nuclear translocation of NF-κB (c-Rel/p65) and
AP-1 expression in a time-dependent manner in ECs. Mutating NF-κB and
AP-1 significantly reduced
histone-induced TF expression. Altogether, our experiments suggest that
histone induces TF expression in ECs via
cell surface receptors TLR4 and TLR2, simultaneously depending on the activation of the
transcription factors NF-κB and
AP-1.