Inflammatory response-mediated Hypercoagulation underlies Concanavalin A-induced severe hepatitis in mice

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Con A treatment induces severe hepatitis in mice in a manner dependent on T cells, IFNγ and TNF. Treatment with the anticoagulant heparin protects against hepatitis despite normal production of IFNγ and TNF. Here, we investigated molecular and cellular mechanisms for hypercoagulation-mediated hepatitis. After Con A challenge liver of wild-type mice showed prompt induction of Ifnγ and Tnf, followed by mRNA expression of tissue factor(TF), which initiate blood coagulation. The mice developed dense intrahepatic fibrin deposition and massive liver necrosis. In contrast, Ifnγ-/-mice and Ifnγ-/-Tnf-/-mice neither induced Tf, nor developed hepatitis. In wild-type mice TF blockade with an anti-TF antibody protected against Con A-induced hepatitis. Both hepatic macrophages and sinusoidal endothelial cells expressed Tf after Con A challenge. Macrophage-depleted wild-type mice reconstituted with hematopoietic cells including macrophages deficient in STAT1 essential for IFNγ signaling, exhibited substantial reduction of hepatic Tf and of liver injuries. This was also true for macrophage-depleted Stat1-/-mice reconstituted with wild-type macrophages. Exogenous IFNγ 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. Collectively, these results strongly suggested that pro-inflammatory signals elicited by IFNγ, TNF and Con A in both hepatic macrophages and sinusoidal endothelial cells are necessary and sufficient for the development of hypercoagulation-mediated hepatitis.