Interferon-gamma-mediated tissue factor expression contributes to T-cell-mediated fulminant hepatitis through induction of hyper coagulation in mice

刀豆蛋白A(ConA)治疗以依赖干扰素(IFN)-γ的方式诱导小鼠暴发型肝炎。正如之前报道的那样，抗凝剂肝素的治疗可以预防Con A肝炎，尽管干扰素-γ的产生是健康的。在此，我们探讨了高凝状态下肝炎的发病机制。缺乏干扰素-γ的小鼠对Con A肝炎具有抵抗力，不会诱导全身和肝脏的高凝。这表明干扰素-γ在血栓相关改变中是必要的。组织因子的中和是凝血级联激活所必需的，在正常诱导干扰素-γ的情况下，对这种肝炎的保护作用是不可避免的。ConA刺激后表达组织因子的肝巨噬细胞和血管内皮细胞均需要对干扰素-γ的反应性。由此可见，干扰素-γ在多种肝细胞中所产生的促炎信号在甲型病毒性肝炎的发生发展中是必需的。

Concanavalin A (Con A) treatment induces fulminant hepatitis in mice in a manner dependent on interferon (IFN)-gamma. As previously reported, treatment with the anticoagulant heparin protects against Con A hepatitis, despite healthy production of IFN-gamma. Here, we investigated the mechanisms for hypercoagulation-mediated hepatitis. Mice deficient in IFN-gamma were resistant to Con A hepatitis without induction of systemic and hepatic hypercoagulation. This suggests that IFN-gamma is necessary for the thrombus-associated changes. Neutralization of tissue factor, that is essential for the activation of coagulation cascade, resulted in the protection of this hepatitis despited normal induction of IFN-gamma. Responsiveness to IFN-gamma was required for both hepatic macrophages and endothelial cells, which expressed tissue factor after Con A challenge. Thus, proinflammatory signal elicited by IFN-gamma in various liver cells is necessary for the development of Con A hepatitis.