title: Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury.
abstract: We previously reported that extracellular histones are major mediators of death in sepsis. Infusion of extracellular histones leads to increased cytokine levels. Histones activate TLR2 and TLR4 in a process that is enhanced by binding to DNA. Activation of TLR4 is responsible for the histone-dependent increase in cytokine levels. To study the impact of histone release on pathology we used two models: a Con A-triggered activation of T cells to mimic sterile inflammation, and acetaminophen to model drug-induced tissue toxicity. Histones were released in both models and anti-histone Abs were protective. TLR2- or TLR4-null mice were also protected. These studies imply that histone release contributes to death in inflammatory injury and in chemical-induced cellular injury, both of which are mediated in part through the TLRs.
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Zhang
authors.forename: Marc
authors.initials: M
authors.lastname: Monestier
authors.forename: Naomi L
authors.initials: NL
authors.lastname: Esmon
authors.forename: Charles T
authors.initials: CT
authors.lastname: Esmon
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D006657:Histones / Q000378:metabolism*; D008099:Liver / Q000293:injuries* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018746:Systemic Inflammatory Response Syndrome / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D006657:Histones; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4