Role of Kupffer cells on chronic liver injury

2010 Fiscal Year Final Research Report

• Project/Area Number: 21790657
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: Gifu University
• Principal Investigator: OSAWA Yosuke Gifu University, 医学系研究科, 助教 (60447787)
• Project Period (FY): 2009 – 2010
• Keywords: 慢性肝障害 / アポトーシス / クッパー細胞 / 肝細胞 / スフィンゴ脂質 / 糖代謝 / 脂質代謝 / 肝再生 / 肝線維化

Research Abstract

Background and Aims : Kupffer cells, resident tissue macrophages of the liver, play a key role in the regulation of hepatic inflammation, hepatocyte death, and fibrosis that characterize liver diseases. However, it is controversial whether Kupffer cell promotes or protects from liver injury. To explore this issue, we examined the role of Kupffer cell in liver injury, cell death, regeneration, and fibrosis on cholestatic liver injury. Methods : A model of partial bile duct ligation (PBDL) was developed. The left hepatic duct of wild-type C57BL/6 male mice was ligated with 6-0 silk, and the animals were sacrificed 10 days after the surgery. Liver injury, regeneration, and fibrosis were compared between the ligated left and non-ligated right lobes. Hepatocyte apoptosis was induced by administration of D-galactosamine and TNF-alpha to the PBDL mice. The effects of Kupffer cell depletion by alendronate liposomes, or inhibition of AKT by adenovirus expressing dominant-negative AKT were investigated. Results : In the cholestatic liver injury, remaining viable cells represented tolerance for tumor necrosis factor (TNF)-α-induced hepatocyte apoptosis and regenerative features along with AKT activation. Inhibition of AKT abolished the survival and regenerative properties in hepatocytes. Moreover, Kupffer cell depletion increased hepatocyte damage and the sensitivity of TNF-α-induced hepatocyte apoptosis in ligated lobes. Kupffer cell depletion decreased hepatocyte regeneration and liver fibrosis with reduced AKT activation. Conclusion: Kupffer cell has a protective role for hepatocyte damage, and promotes cell survival, liver regeneration, and fibrosis in cholestatic liver disease. Kupffer cell is crucial for AKT activation of hepatocytes that is required for the survival and regenerative responses.

Research Products

• [Journal Article] Imaging the recruitment of cancer-associated fibroblasts by liver-metastatic colon cancer. (2011)
  • Author(s): Suetsugu, A., Osawa, Y., Nagaki, M., Saji, S., Moriwaki, H., Bouvet, M., Hoffman, R.M.
  • Journal Title: J Cell Biochem. 112 Pages: 949-953
  • Peer Reviewed
• [Journal Article] Ability of IDO to attenuate liver injury in alpha-galactosylceramide-induced hepatitis model. (2010)
  • Author(s): Ito, H., Hoshi, M., Ohtaki, H., Taguchi, A., Ando, K., Ishikawa, T., Osawa, Y., Hara, A., Moriwaki, H., Saito, K., Seishima, M.
  • Journal Title: J Immunol. 185 Pages: 4554-4550
  • Peer Reviewed
• [Journal Article] The absence of IDO upregulates type I IFN production, resulting in suppression of viral replication in the retrovirus-infected mouse. (2010)
  • Author(s): Hoshi, M., Saito, K., Hara, A., Taguchi, A., Ohtaki, H., Tanaka, R., Fujigaki, H., Osawa, Y., Takemura, M., Matsunami, H., Ito, H., Seishima, M.
  • Journal Title: J Immunol. 185 Pages: 3305-3312
  • Peer Reviewed
• [Journal Article] Simultaneous color-coded imaging to distinguish cancer "stem-like" and non-stem cells in the same tumor. (2010)
  • Author(s): Suetsugu, A., Osawa, Y., Nagaki, M., Moriwaki, H., Saji, S., Bouvet, M., Hoffman, R.M.
  • Journal Title: J Cell Biochem. 111 Pages: 1035-1041
  • Peer Reviewed
• [Journal Article] Role of acid sphingomyelinase of Kupffer cells in cholestatic liver injury in mice. (2010)
  • Author(s): Osawa, Y., Seki, E., Adachi, M., Suetsugu, A., Ito, H., Moriwaki, H., Seishima, M., Nagaki, M.
  • Journal Title: Hepatology. 51 Pages: 237-245
  • Peer Reviewed
• [Journal Article] (-)-Epigallocatechin gallate prevents carbon tetrachloride-induced rat hepatic fibrosis by inhibiting the expression of the PDGFRbeta and IGF-1R. (2009)
  • Author(s): Yasuda, Y., Shimizu, M., Sakai, H., Iwasa, J., Kubota, M., Adachi, S., Osawa, Y., Tsurumi, H., Hara, Y., Moriwaki, H.
  • Journal Title: Chem Biol Interact. 182 Pages: 159-164
  • Peer Reviewed
• [Journal Article] Interaction between LPS-induced NO production and IDO activity in mouse peritoneal cells in the presence of activated Valpha14 NKT cells. (2009)
  • Author(s): Ohtaki, H., Ito, H., Ando, K., Ishikawa, T., Hoshi, M., Tanaka, R., Osawa, Y., Yokochi, T., Moriwaki, H., Saito, K., Seishima, M.
  • Journal Title: Biochem Biophys Res Commun. 389 Pages: 229-234
  • Peer Reviewed
• [Journal Article] Extracellular matrix is required for the survival and differentiation of transplanted hepatic progenitor cells. (2009)
  • Author(s): Tsukada, Y., Nagaki, M., Suetsugu, A., Osawa, Y., Moriwaki, H.
  • Journal Title: Biochem Biophys Res Commun 381 Pages: 733-737
  • Peer Reviewed
• [Journal Article] Sphingosine kinase isoforms regulate oxaliplatin sensitivity of human colon cancer cells through ceramide accumulation and AKT activtion. (2009)
  • Author(s): Nemoto, S., Nakamura, M., Osawa, Y., Kono, S., Itoh, Y., Okano, Y., Murate, T., Hara, A., Ueda, H., Nozawa, Y., Banno, Y.
  • Journal Title: J Biol Chem (in print)
  • Peer Reviewed
• [Journal Article] Antiapoptotic effect of c-Jun N-terminal Kinase-1 through Mcl-1 stabilization in TNF-induced hepatocyte apoptosis. (2009)
  • Author(s): Kodama, Y., Taura, K., Miura, K., Schnabl, B., Osawa, Y., Brenner, D.A.
  • Journal Title: Gastroenterology 136 Pages: 1423-1434
  • Peer Reviewed
• [Journal Article] Acid sphingomyelinase regulates glucose and lipid metabolism in hepatocytes through AKT activation and AMP-activated protein kinase suppression.
  • Author(s): Osawa, Y., Seki, E., Kodama, Y., Suetsugu, A., Miura.K., Adachi, M., Ito, H., Shirator,i Y., Banno, Y., Olefsky, J.M., Nagaki, M., Moriwaki, H., Brenner, D.A., Seishima, M.
  • Journal Title: FASEB J. in press.
  • Peer Reviewed
• [Presentation] Roles of acid sphingomyelinase on glucose and lipid metabolism in hepatocytes. (2011)
  • Author(s): Osawa Y, Nagaki M, Yasuda Y, Moriwaki H, Seishima M
  • Organizer: Asian Pacific Association for the Study of the Liver (APASL) 2011.
  • Place of Presentation: Bangkok.Thailand
  • Year and Date: 20110000
• [Presentation] A lipophilic statin, pitavastatin, suppresses azoxymethane-induced and obesity-related colonic premalignant lesions in male db/db mice. (2011)
  • Author(s): Yasuda Y, Shimizu M, Sakai H, Kubota M, Osawa Y, Moriwaki H
  • Organizer: Asian Pacific Association for the Study of the Liver (APASL) 2011.
  • Place of Presentation: Bangkok.Thailand
  • Year and Date: 20110000
• [Presentation] Color-coded imaging of tumor growth, metastasis and drug resistance of co-implanted cancer stem cells and non-cancer stem cells. (2010)
  • Author(s): Suetsugu A, Osawa Y, Nagaki M, Moriwaki H, Bouvet M, Hoffman RM
  • Organizer: American association of cancer research 101^<st> annual meeting 2010.
  • Place of Presentation: Washington DC USA
  • Year and Date: 20100000
• [Presentation] Use of RFP and GFP transgenic nude mice to study the tumor microenvironment of metastasis. (2010)
  • Author(s): Suetsugu A, Osawa Y, Nagaki M, Saji S, Moriwaki H, Momiyana M, Bouvet M, Hoffman RM
  • Organizer: American association of cancer research 101^<st> annual meeting 2010.
  • Place of Presentation: Washington DC USA
  • Year and Date: 20100000
• [Presentation] Inhibition of acid sphingomyelinase causes hepatic glucose intolerance and insulin resistance. (2010)
  • Author(s): Osawa Y, Ito H, Suetsugu A, Nagaki M, Moriwaki H, Seishima M
  • Organizer: Digestive Disease Week (DDW) 2010.
  • Place of Presentation: New Orleans USA
  • Year and Date: 20100000
• [Presentation] An analysis of CD133 positive bone marrow in oval cell induced model and a role of CD133 bone marrow in mice with liver fibrosis. (2010)
  • Author(s): Suetsugu A, Nagaki M, Osawa Y, Hoffman RM, Moriwaki H
  • Organizer: Digestive Disease Week (DDW) 2010.
  • Place of Presentation: New Orleans USA
  • Year and Date: 20100000
• [Presentation] Role of Kupffer cells in cholestatic liver injury in mice. (2010)
  • Author(s): Osawa Y, Nagaki M, Yasuda Y, Tsukada Y, Moriwaki H, Seishima M
  • Organizer: Asian Pacific Association for the Study of the Liver (APASL) 2010.
  • Place of Presentation: Beijin.China
  • Year and Date: 20100000
• [Presentation] Extracellular matrix is required for the survival and differentiation of transplanted hepatic progenitor cells. (2010)
  • Author(s): Tsukada Y, Nagaki M, Suetsugu A, Osawa Y, Moriwaki H
  • Organizer: Asian Pacific Association for the Study of the Liver (APASL) 2010.
  • Place of Presentation: Beijing.China
  • Year and Date: 20100000
• [Presentation] (-)-Epigallocatechin gallate prevents carbon tetrachloride-induced rat hepatic fibrosis by inhibiting the expression of the PDGFR and IGF-1R. (2010)
  • Author(s): Yasuda Y, Shimizu M, Sakai H, Kubota M, Osawa Y, Hara Y, Moriwaki H
  • Organizer: Asian Pacific Association for the Study of the Liver (APASL) 2010.
  • Place of Presentation: Beijing.China
  • Year and Date: 20100000
• [Presentation] パネルディスカッション「肝臓の再生機構を考える:今後の肝再生医療への展望」肝細胞死と肝再生・肝線維化連携機構におけるKupffer細胞の役割 (2010)
  • Author(s): 大澤陽介, 永木正仁, 森脇久隆
  • Organizer: 第14回日本肝臓学会大会
  • Place of Presentation: 横浜
  • Year and Date: 20100000
• [Presentation] Anti-apoptotic effects against TNF-alpha treatment in bile duct ligated mouse liver. (2009)
  • Author(s): Osawa Y, Nagaki M, Ito H, Seishima M, Moriwaki H
  • Organizer: Digestive Disease Week (DDW) 2009.
  • Place of Presentation: Chicago USA
  • Year and Date: 20090000
• [Presentation] ワークショップ「免疫担当細胞異常からみた肝疾患の動態」胆管結紮誘導性慢性肝障害マウスモデルにおけるKupffer細胞の役割 (2009)
  • Author(s): 大澤陽介, 永木正仁, 森脇久隆
  • Organizer: 第13回日本肝臓学会大会
  • Place of Presentation: 京都
  • Year and Date: 20090000
• [Presentation] パネルディスカッション「自然免疫と消化器疾患」TLR4-MyD88-NFκBシグナルによる肝 星細胞活性化と肝線維症における役割 (2009)
  • Author(s): 石亦宏, 大澤陽介, 藤本治朗
  • Organizer: 第13回日本肝臓学会大会
  • Place of Presentation: 京都
  • Year and Date: 20090000
• [Book] 2nd edition of Essentials of Apoptosis. Part III Apoptosis in mammalian physiology and pathogenesis. Chapter 24 Apoptosis in liver injury and liver diseases. (2009)
  • Author(s): Osawa, Y., Seki, E., Brenner DA.
  • Total Pages: 547-564,17
  • Publisher: Springer