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Molecular mechanism of inflammatory cytokine induction by hepatitis viruses

Research Project

Project/Area Number 12670462
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionThe University of Tokyo

Principal Investigator

KATO Naoya  University of Hospital, The University of Tokyo, Research Associate, 医学部・附属病院, 助手 (90313220)

Co-Investigator(Kenkyū-buntansha) KANAI Fumihiko  University of Hospital, The University of Tokyo, Research Associate, 医学部・附属病院, 助手 (70334399)
SHIRATORI Yasushi  University of Hospital, The University of Tokyo, Associate Professor, 医学部・附属病院, 講師 (70196624)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2000: ¥2,100,000 (Direct Cost: ¥2,100,000)
KeywordsHepatitis B virus (HBV) / Hepatitis C virus (HCV) / Hepatitis delta virus (HDV) / Inflammatory cytokine / Apoptosis / NF-_KB / Interleukin / p53 / MAPK / Bcl-x_L / 翻訳 / D型肝炎ウイルス / p21
Research Abstract

Hepatitis viruses cause persistent infection, chronic hepatitis, cirrhosis, and hepatocellular carcinoma. In this study, the influence of hepatitis B, C, and delta virus (HBV, HCV, and HDV, respectively) proteins on the function of hepatocyte, especially the induction of inflammatory cytokines, was investigated. Among 15 viral proteins, HCV core protein activated NF-_KB, AP-1, MAP kinase, and P53-associated signaling pathways. HCV core protein upregulated interleukin-16 and -8 promoters through NF-_KB activation, and increased p21 expression through p53 activation. The core protein activated NF-_KB pathway through IKKβand tumor necrosis factor receptor-associated factor (TRAF), and enhanced p53 function through augmentation of DNA-binding affinity and transcriptional ability. The core protein may directly promote cell proliferation and induce an inflammatory reaction by activating NF-_KB, AP-1, and MAP kinase-assosiated signaling pathways. On the other hand, the core protein could enha … More nce p53 function. These opposing functions may result in exquisitely balancing the proliferation of hepatocytes infected with HCV.
Apoptosis is related to inflammation of the liver in chronic hepatitis. In HCV core protein-expressing cell, activation of caspase 3 was inhibited and Bcl-x_L expression was increased. The core protein enhances the Bcl-x_L expression through activating MAP kinase cascade, and thus inhibits apoptotic signal induced by Fas at the mitochondria level. Core protein-mediated Bcl-x_L induction may be one of the mechanisms underlying its inhibition of apoptosis, which might contribute to the pathogenesis of HCV.
HCV NS4A and NS4B proteins generally suppressed cellular translation process (translational shutoff). This function may be involved in HCV infection and help its survival in host cells. In addition to HCV proteins, HDV large antigen activated SRF-associated pathway and synergistically activated SRE with HBx protein.
In summary, hepatitis virus proteins may influence intracellular signaling pathways, induce inflammatory cytokines, and thus cause inflammation of the liver. Less

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (26 results)

All Other

All Publications (26 results)

  • [Publications] Kato N et al.: "Activation of intracelluar signaling by hepatity B & C viruses : C-viral core is the most potent signal inducer"Hepatology. 32. 405-412 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Otsuka M et al.: "Hepatitis C virus core protein erburres p53 function through augmentation of DNA-binding affinity & transcriptional ability"J Biol Chem. 275. 34122-34130 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Goto T et al.: "Large isoporm of hepatitis cleeta antigen aetivates SRF associated transcription"J Biol Chem. 275. 37311-37316 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yoshida H et al.: "Hepatitis C virus core protein activates NF-kB olepencleat signaling through-TRAF"J Biol Chem. 276. 16399-16405 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ono SK et al.: "The polyuredose L528M nutation cooperates with-nucleotide bind ring site mutation increasing HBV replication & drug"J Clin Invest. 107. 449-455 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kato J et al.: "Hepatitis C virus NS4A and NS4B protein suppress translation in vivo"J Med Viral. 66. 187-199 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kato N et al.: "Growth, proliferation, and apoptosis in hepatocytes"Springer-Verlag Tokyo. 81-98 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kato N, Yoshida H, Ono-Nita SK, Kato J, Goto T, Otsuka M, Lan K-H, Matsushima K, Shiratori Y, Omata M: "Activation of intracellular signaling by hepatitis B and C viruses : C-viral core is the most potent signal indexer"Hepatology. 32. 405-412 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Otsuka M, Kato N, Lan K-H, Yoshida H, Kato J, Goto T, Shiratori Y, Omata M: "Hepatitis C virus core protein enhances p53 function through augmentation of DNA-binding affinity and transcriptional ability"J. Biol Chem. 275. 34122-34130 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Goto T, Kato N, Ono-Nita SK, Yoshida H, Otsuka M, Shiratori Y, Omata M: "Large isoform of hepatitis delta antigen activates serum response factor associated transcription"J Biiol Chem. 275. 37311-3736 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yoshida H, Kato N, Shiratori Y, Otsuka M, Maeda S, Kato J, Omata M: "Hepatitis C virus core protein activates NF-_KB-dependent signaling through tumor necrosis factor receptor-associated factor"J. Biol Chem. 276. 16399-16405 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ono SK, Kato N, Shiratori Y, Kato J, Goto T, Scinazi RF, Carrilho FJ, Omata M: "The polymerase L528M mutation cooperates with nucleotide binding-site mutations, increasing hepatitis B virus replication and drug resistance"J Clin Invest. 107. 449-455 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kato J, Kato N, Yoshida H, Ono-Nita SK, Shiratori Y, Omata M: "Hepatitis C virus NS4A and NS4B proteins suppress translation in vivo"J Med Virol. 66. 187-199 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kato N, Yoshida H, Ohtsuka M, Shiratori Y, Omata M: "Induction of proliferation-related singnals by hepatitis C virus. In : Okita K ed. Growth, poliferation, and apoptosis in hepatocytes"Springer-Verlag Tokyo. 81-98 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yoshida H, et al.: "Hepatitis virus core protein activates NF-κB-dependent signaling through TRAF"J Biol Chem. 276. 16399-16405 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Goto T, et al.: "Large isoform of hepatitis delta antigen activates the rat smooth muscle (sm) 22alpha promoter via enhancement of transcriptional ability of serum response factor"Cells of the Hepatic Sinusoid. 8. 223-224 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ono-Nita SK, et al.: "Current options for the theropy of chisue hepatitis B inpection"Clin Infect Dis Rep. 3. 137-142 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kato J, et al.: "hepatitis c-virus NS4A and NS4B proteins suppress trouslation in vivo"J Med Vivol. 66. 187-199 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Otsuka M, et al.: "Hepatitis C-virus core protein inhibits apoptosis via enhanced Bcl-x_L expression"Vivology. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kato N et al.: "Growth proliferation, and apoptosis in hepatocytes"Springer Verlag Tokyo. 100 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kato N,Yoshida H, et al.: "Activation of intracellular signaling by hepatitis B and C viruses."Hepatology. 32. 405-412 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Otsuka M,Kato N, et al.: "Hepatitis C virus core protein enhances p53 function through augmentation of DNA-binding affinity and transcriptorial"J Biol Chem. 275. 34122-34130 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Goto T,Kato N, et al.: "Large isoforn of hepatitis delfa antigen activates serum response factor associated transeription."J Biol Chem. 275. 37311-37316 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ono-Nita SK,Kato N, et al.: "The polymerase L528M nutation cooperates with nucleotide binding-site mutations, increasing HBV replication and drug resistance"J Clin Inrest. 107. 449-455 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Goto T,Kato N, et al.: "Large isoform of hepatitis delta autigen activates the rat SM22α proccufer via enhancement of transcriptional abiling of SRF."Cells of the Hepatic Simsoid. 8(in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yoshida H,Kato N, et al.: "Hepatics C virus core protein activates NF-KB dependent signaling through TNFR・associated Factor."J Biol Chem. 276(in press). (2001)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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