title: 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.
authors.affiliation: Department of Microbiology, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Kato
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Okamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Motoyama
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Uchiyama
authors.forename: Daniel
authors.initials: D
authors.lastname: Kirchhofer
authors.forename: Nico
authors.initials: N
authors.lastname: Van Rooijen
authors.forename: Hirayuki
authors.initials: H
authors.lastname: Enomoto
authors.forename: Shuhei
authors.initials: S
authors.lastname: Nishiguchi
authors.forename: Norifumi
authors.initials: N
authors.lastname: Kawada
authors.forename: Jiro
authors.initials: J
authors.lastname: Fujimoto
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tsutsui
mesh_terms: D000818:Animals; D003208:Concanavalin A; D042783:Endothelial Cells / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D006520:Hepatitis, Animal / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008934:Mitogens; D009336:Necrosis; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology; D019851:Thrombophilia / Q000139:chemically induced / Q000150:complications*; D013925:Thromboplastin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D008934:Mitogens; D017395:Plasminogen Activator Inhibitor 1; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D007371:Interferon-gamma; D005337:Fibrin; D013925:Thromboplastin