These authors equally contributed to the present study.
Article first published online: 7 JAN 2013
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 1, pages 362–372, January 2013
How to Cite
Kato, J., Okamoto, T., Motoyama, H., Uchiyama, R., Kirchhofer, D., Van Rooijen, N., Enomoto, H., Nishiguchi, S., Kawada, N., Fujimoto, J. and Tsutsui, H. (2013), Interferon-gamma–mediated tissue factor expression contributes to T-cell-mediated hepatitis through induction of hypercoagulation in mice. Hepatology, 57: 362–372. doi: 10.1002/hep.26027
Potential conflict of interest: Nothing to report.
This work was supported, in part, by JSPS KAKENHI (grant nos.: 22659328, 24659806, and 23659660) and a Hitec Research Center Grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
- Issue published online: 7 JAN 2013
- Article first published online: 7 JAN 2013
- Accepted manuscript online: 22 AUG 2012 03:23AM EST
- Manuscript Accepted: 5 AUG 2012
- Manuscript Received: 12 APR 2012
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)