title: Extracellular histones induce tissue factor expression in vascular endothelial cells via TLR and activation of NF-κB and AP-1.
abstract: 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.
authors.affiliation: Department of Haematology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Haematology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Haematology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Haematology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
authors.forename: Ben
authors.initials: B
authors.lastname: Lv
authors.affiliation: Department of Haematology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Department of Hemotology Xiangya Hospital, Central South University Changsha, Hunan 410078, PR China. Electronic address: hope058@163.com.
authors.forename: Fangping
authors.initials: F
authors.lastname: Chen
mesh_terms: D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology*; D045604:Extracellular Fluid / Q000276:immunology; D006657:Histones / Q000008:administration & dosage* / Q000276:immunology; D006801:Humans; D016328:NF-kappa B / Q000276:immunology*; D013925:Thromboplastin / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000276:immunology*
chemical_list: D006657:Histones; D016328:NF-kappa B; D051193:Toll-Like Receptors; D018808:Transcription Factor AP-1; D013925:Thromboplastin
keywords: Histones; Thrombosis; Tissue factor