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

• Project/Area Number: 24659806
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Emergency medicine
• Research Institution: Hyogo Medical University
• Principal Investigator: TSUTSUI Hiroko 兵庫医科大学, 医学部, 教授 (40236914)
• Co-Investigator(Renkei-kenkyūsha): UCHIYAMA Ryosuke 兵庫医科大学, 医学部, 講師 (20456891)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 劇症肝炎 / Concanavalin A / 微小循環傷害 / 組織因子 / interferon gamma / Tumor necrosis factor / クッパー細胞 / 肝類洞内皮細胞 / Interferon gamma / Tumor Necrosis Factor / 血栓性肝炎 / STAT1 / Kupffer細胞 / 類洞内皮細胞

Research Abstract

Concanavalin A (Con A) treatment induces fulminant hepatitis in mice in a manner dependent on interferon (IFN)-gamma. As previously reported, treatment with the anticoagulant heparin protects against Con A hepatitis, despite healthy production of IFN-gamma. Here, we investigated the mechanisms for hypercoagulation-mediated hepatitis. Mice deficient in IFN-gamma were resistant to Con A hepatitis without induction of systemic and hepatic hypercoagulation. This suggests that IFN-gamma is necessary for the thrombus-associated changes. Neutralization of tissue factor, that is essential for the activation of coagulation cascade, resulted in the protection of this hepatitis despited normal induction of IFN-gamma. Responsiveness to IFN-gamma was required for both hepatic macrophages and endothelial cells, which expressed tissue factor after Con A challenge. Thus, proinflammatory signal elicited by IFN-gamma in various liver cells is necessary for the development of Con A hepatitis.

Research Products

• [Journal Article] Importance of Kupffer cells in the development of acute liver injuries in mice (2014)
  • Author(s): Tsutsui H, Nishiguchi S
  • Journal Title: Int J Mol Sci Volume: 5 Issue: 5 Pages: 7711-7730
  • DOI: 10.3390/ijms15057711
  • Peer Reviewed
• [Journal Article] Interferon-gamma-mediated tissue factor expression contributes to T-cell-mediated hepatitis through induction of hyper coagulation in mice (2013)
  • Author(s): Kato J, Okamoto T, Motoyama H, Uchiyam R, Kirchhofer D, van Rooijen N, Enomoto H, Nishiguchi S, Kawada N, Fujimoto J, H Tsutsui
  • Journal Title: Hepatology Volume: 57 Issue: 1 Pages: 362-372
  • DOI: 10.1002/hep.26027
  • Peer Reviewed
• [Journal Article] Interferon-gamma-mediated tissue factor expression contributes to T-cell-mediated hepatitis through induction of hypercoagulation in mice (2012)
  • Author(s): Kato J, Okamoto T, Motoyama H, Uchiyama R, Kirchhofer D, van Rooijen N, Enomoto H, Nishiguchi S, Kawada N, Fujimoto J, Tsutsui H
  • Journal Title: Hepatology Volume: 57 Pages: 362-372
  • Peer Reviewed
• [Presentation] Contribution of IFN-γ/STAT1 signaling to T cell-mediated hepatitis though induction of hepatic hypercoagulation status (2012)
  • Author(s): Tsutsui H
  • Organizer: IEIIS 2012
  • Place of Presentation: 東京
  • Year and Date: 2012-10-26
• [Presentation] Concanavalin A重症肝炎の責任病態である肝局所DICにおける,IFNγ/STAT1に依存した組織因子発現誘導の重要性 (2012)
  • Author(s): 岡本共弘, 内山良介, 西口修平, 筒井ひろ子
  • Organizer: 第77回日本インターフェロン・サイトカイン学会学術集会
  • Place of Presentation: 神戸
• [Presentation] Contribution of IFN-γ/STAT1 signaling to T cell-mediated hepatitis through induction of hepatic hypercoagulation status. (Symposium) (2012)
  • Author(s): Tsutsui H.
  • Organizer: The 12th Biennial International Endotoxin & Innate Immunity Society Meeting (IEIIS2012)
  • Place of Presentation: 東京
  • Invited
• [Presentation] IFNγ/STAT1-mediated tissue factor expression contributes to T cell-mediated hepatitis via induction of hypercoagulation in mice. (2012)
  • Author(s): Okamoto T, Uchiyama R, Tsutsui H.
  • Organizer: 第41回日本免疫学会総会・学術集会 (ワークショップ)
  • Place of Presentation: 神戸
• [Remarks]
  • URL: http://www.hyo-med.ac.jp/research_facilities/output/gyoseki/20131002.html
• [Remarks] Hepatology誌に論文が掲載されました
  • URL: http://www.hyo-med.ac.jp/research_facilities/output/gyoseki/20131002.html
• [Remarks] 兵庫医科大学
  • URL: http://www.hyo-med.ac.jp/faculty/course/microbiology.html