Interferon-gamma-mediated tissue factor expression contributes to T-cell-mediated hepatitis through induction of hypercoagulation in mice
Interferon-gamma-mediated tissue factor expression contributes to T-cell-mediated hepatitis through induction of hypercoagulation in mice
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DOI：
10.1002/hep.26027
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发表时间：
2013-01-01
期刊：
影响因子：
13.5
通讯作者：
Tsutsui, Hiroko
中科院分区：
文献类型：
--
作者：
Kato, Junko;Okamoto, Tomohiro;Tsutsui, Hiroko
刀豆球蛋白 A (Con A) 治疗会以依赖于 T 细胞、干扰素 (IFN)-γ 和肿瘤坏死因子 (TNF) 的方式诱导小鼠严重肝炎。尽管 IFN-α 的产生正常，但抗凝肝素治疗可预防肝炎。和肿瘤坏死因子。在这里，我们研究了高凝介导的肝炎的分子和细胞机制。 Con A 攻击后，野生型 (WT) 小鼠的肝脏显示出即时诱导的 Ifn?和 Tnf，其次是组织因子 (TF) 和纤溶酶原激活剂抑制剂-1 (PAI-1) 的信使 RNA 表达，分别启动血液凝固和抑制血栓溶解。小鼠肝内出现致密纤维蛋白沉积和大量肝坏死。相比之下，Ifn?-/-小鼠和Ifn?-/-Tnf-/-小鼠既不诱导Pai1或Tf，也不发展肝炎。在WT小鼠中，用抗TF单克隆抗体阻断TF可以防止Con A诱导的肝炎，而Pai1-/-小鼠则没有受到保护。 Con A 攻击后，肝巨噬细胞和肝窦内皮细胞 (EC) 均表达 Tf。巨噬细胞耗尽的 WT 小鼠用造血细胞重建，其中巨噬细胞缺乏 IFN-α 必需的信号转导器和转录激活剂 1 (STAT1)。信号传导，表现出肝脏 Tf 和肝损伤的显着降低。对于用 WT 巨噬细胞重建的巨噬细胞耗尽的 Stat1-/- 小鼠也是如此。外源性干扰素-? TNF 导致 T 细胞缺失、缺乏重组激活基因 2 的 Con A 抗性小鼠，非常容易受到 Con A 引起的涉及 TF 的肝损伤。结论：总的来说，这些结果强烈表明，肝巨噬细胞和肝窦 EC 中 IFN-α、TNF 和 Con A 引发的促炎信号对于高凝介导的肝炎的发展是必要且充分的。 （肝病学 2013；57：362-372）
Concanavalin A (Con A) treatment induces severe hepatitis in mice in a manner dependent on T cells, interferon (IFN)-gamma, and tumor necrosis factor (TNF). Treatment with the anticoagulant heparin protects against hepatitis, despite healthy production of IFN-? and TNF. Here, we investigated molecular and cellular mechanisms for hypercoagulation-mediated hepatitis. After Con A challenge, liver of wild-type (WT) mice showed prompt induction of Ifn? and Tnf, followed by messenger RNA expression of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1), which initiate blood coagulation and inhibit clot lysis, respectively. Mice developed dense intrahepatic fibrin deposition and massive liver necrosis. In contrast, Ifn?-/- mice and Ifn?-/-Tnf-/- mice neither induced Pai1 or Tf nor developed hepatitis. In WT mice TF blockade with an anti-TF monoclonal antibody protected against Con Ainduced hepatitis, whereas Pai1-/- mice were not protected. Both hepatic macrophages and sinusoidal endothelial cells (ECs) expressed Tf after Con A challenge. Macrophage-depleted WT mice reconstituted with hematopoietic cells, including macrophages deficient in signal transducer and activator of transcription-1 (STAT1) essential for IFN-? signaling, exhibited substantial reduction of hepatic Tf and of liver injuries. This was also true for macrophage-depleted Stat1-/- mice reconstituted with WT macrophages. Exogenous IFN-? and TNF rendered T-cell-null, Con Aresistant mice deficient in recombination-activating gene 2, highly susceptible to Con Ainduced liver injury involving TF. Conclusions: Collectively, these results strongly suggest that proinflammatory signals elicited by IFN-?, TNF, and Con A in both hepatic macrophages and sinusoidal ECs are necessary and sufficient for the development of hypercoagulation-mediated hepatitis. (HEPATOLOGY 2013; 57:362-372)