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

Abstract

UNLABELLED:

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: Junko Kato, Tomohiro Okamoto, Hiroyuki Motoyama, Ryosuke Uchiyama, Daniel Kirchhofer, Nico Van Rooijen, Hirayuki Enomoto, Shuhei Nishiguchi, Norifumi Kawada, Jiro Fujimoto, Hiroko Tsutsui
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 57 Issue 1 Pg. 362-72 (Jan 2013) ISSN: 1527-3350 [Electronic] United States
• PMID: 22936459 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 American Association for the Study of Liver Diseases.

Chemical References

• Mitogens
• Plasminogen Activator Inhibitor 1
• STAT1 Transcription Factor
• Stat1 protein, mouse
• Tumor Necrosis Factor-alpha
• Concanavalin A
• Interferon-gamma
• Fibrin
• Thromboplastin

Topics

• Animals
• Concanavalin A
• Endothelial Cells (metabolism)
• Fibrin (metabolism)
• Hepatitis, Animal (etiology, metabolism, pathology)
• Interferon-gamma (metabolism)
• Liver (immunology, metabolism, pathology)
• Macrophages (metabolism)
• Mice
• Mice, Knockout
• Mitogens
• Necrosis
• Plasminogen Activator Inhibitor 1 (metabolism)
• STAT1 Transcription Factor (metabolism)
• Signal Transduction
• T-Lymphocytes (physiology)
• Thrombophilia (chemically induced, complications)
• Thromboplastin (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)