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

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)

Betulin from Hedyotis hedyotidea ameliorates concanavalin A-induced and T cell-mediated autoimmune hepatitis in mice

“…Betulin reduces serum levels of IFN-γ, TNF-α, and IL-6 in mice with hepatitis Several lines of evidence suggest that IFN-γ [16,17] , TNF-α [18,19] , IL-4 [20] , and IL-17 [21,22] promote hepatic damage, whereas IL-10 [23] protects the liver from injury, and IL-6 [18] has varying effects depending on the stage of Con A-induced hepatitis at which it is present. To ascertain whether betulin interfered with the systemic levels of these cytokines, we examined the serum levels of IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10, and IL-17 by using a CBA kit.…”

“…In Con A-induced hepatitis, the inflammatory response is responsible for liver damage and is mainly driven by proinflammatory Th1 cytokines. High levels of proinflammatory cytokines such as TNF-α [18,19] and IFN-γ [16] have been shown to promote the progress of this disease. In addition, neutralizing or knocking out the secretion of these cytokines leads to animal resistance to Con A-induced hepatic damage.…”

Dexmedetomidine premedication attenuates concanavalin A-induced hepatitis in mice

“…To elucidate the cellular source for the high level of circulating IFN-γ and TNF-α, previous studies demonstrated that CD4 + T cells were the main source of increased IFN-γ Kato et al, 2013) and TNF-α (Kato et al, 2013) after Con A challenge. Our study demonstrated that DEX pretreatment inhibited IκBα and p65 phosphorylation in Con A-induced hepatitis.…”

Importance of Kupffer Cells in the Development of Acute Liver Injuries in Mice

“…Inhibition of the coagulation cascade can potently rescue mice from Con A hepatitis without impairment in the induction of IFN-γ and TNF [54]. Very recently, we identified the cellular and molecular mechanisms for the development of Con A-induced acute prothrombotic liver failure [55]. …”