Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
J Immunol. 2011 Sep 1;187(5):2626-31. doi: 10.4049/jimmunol.1003930. Epub 2011 Jul 22.
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.
我们之前报道过细胞外组蛋白是脓毒症中导致死亡的主要介质。细胞外组蛋白的输注会导致细胞因子水平升高。组蛋白通过与 DNA 结合来激活 TLR2 和 TLR4，该过程会增强激活。TLR4 的激活负责组蛋白依赖性细胞因子水平的增加。为了研究组蛋白释放对病理学的影响，我们使用了两种模型：用 ConA 触发 T 细胞激活来模拟无菌性炎症，用对乙酰氨基酚来模拟药物引起的组织毒性。在这两种模型中都释放了组蛋白，并且抗组蛋白 Abs 具有保护作用。TLR2 或 TLR4 缺失的小鼠也受到了保护。这些研究表明，组蛋白释放导致炎症损伤和化学诱导的细胞损伤中的死亡，这两种损伤部分通过 TLR 介导。
