Interferon‐gamma–mediated tissue factor expression contributes to T‐cell‐mediated hepatitis through induction of hypercoagulation in mice123. Issue 1 (7th January 2013) - Kato, Junko
Abstract 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‐γ 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 Ifnγ 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, Ifnγ−/− mice and Ifnγ−/−Tnf−/− mice neither induced Pai1 or Tf nor developed hepatitis. In WT mice TF blockade with an anti‐TF monoclonal antibody protected against Con A–induced 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‐γ 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‐γ and TNF rendered T‐cell‐null, Con A–resistant mice deficient in recombination‐activating gene 2, highly susceptible to Con A–induced liver injury involving TF. Conclusions: Collectively, these results strongly suggest that proinflammatory signals elicited by IFN‐γ, TNF, and Con A in both hepatic macrophages and sinusoidal ECs are necessary and sufficient for the development of hypercoagulation‐mediated hepatitis. (HEPATOLOGY 2013)