Journal of Gastroenterology

, Volume 44, Issue 8, pp 856–863 | Cite as

Interferon-α-induced mTOR activation is an anti-hepatitis C virus signal via the phosphatidylinositol 3-kinase-Akt-independent pathway

  • Azusa Matsumoto
  • Tatsuki Ichikawa
  • Kazuhiko Nakao
  • Hisamitsu Miyaaki
  • Kumi Hirano
  • Masumi Fujimito
  • Motohisa Akiyama
  • Satoshi Miuma
  • Eisuke Ozawa
  • Hidetaka Shibata
  • Shigeyuki Takeshita
  • Hironori Yamasaki
  • Masanori Ikeda
  • Nobuyuki Kato
  • Katsumi Eguchi
Original Article—Liver, Pancreas, and Biliary Tract

Abstract

Object

The interferon-induced Jak-STAT signal alone is not sufficient to explain all the biological effects of IFN. The PI3-K pathways have emerged as a critical additional component of IFN-induced signaling. This study attempted to clarify that relationship between IFN-induced PI3-K-Akt-mTOR activity and anti-viral action.

Result

When the human normal hepatocyte derived cell line was treated with rapamycin (rapa) before accretion of IFN-α, tyrosine phosphorylation of STAT-1 was diminished. Pretreatment of rapa had an inhibitory effect on the IFN-α-induced expression of PKR and p48 in a dose dependent manner. Rapa inhibited the IFN-α inducible IFN-stimulated regulatory element luciferase activity in a dose-dependent manner. However, wortmannin, LY294002 and Akt inhibitor did not influence IFN-α inducible luciferase activity. To examine the effect of PI3-K-Akt-mTOR on the anti-HCV action of IFN-α, the full-length HCV replication system, OR6 cells were used. The pretreatment of rapa attenuated its anti-HCV replication effect in comparison to IFN-α alone, whereas the pretreatment with PI3-K inhibitors, wortmannin and LY294002 and Akt inhibitor did not influence IFN-induced anti-HCV replication.

Conclusion

IFN-induced mTOR activity, independent of PI3K and Akt, is the critical factor for its anti-HCV activity. Jak independent mTOR activity involved STAT-1 phosphorylation and nuclear location, and then PKR is expressed in hepatocytes.

Keywords

mTOR STAT-1 Interferon HCV PKR 

Abbreviations

IFN

Interferon

HCV

Hepatitis C virus

STAT

Signal transducers and activators of transcription

ISGF-3

IFN-stimulated gene factor 3

ISRE

IFN-stimulated regulatory element

PKR

Double-stranded RNA-dependent protein kinase

Rapa

Rapamycin

PI3-K

Phosphatidylinositol 3-kinase

mTOR

Mammalian target of rapamycin

siRNA

Small interfering RNA

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Copyright information

© Springer 2009

Authors and Affiliations

  • Azusa Matsumoto
    • 1
  • Tatsuki Ichikawa
    • 2
  • Kazuhiko Nakao
    • 2
  • Hisamitsu Miyaaki
    • 2
  • Kumi Hirano
    • 1
  • Masumi Fujimito
    • 2
  • Motohisa Akiyama
    • 2
  • Satoshi Miuma
    • 2
  • Eisuke Ozawa
    • 2
  • Hidetaka Shibata
    • 2
  • Shigeyuki Takeshita
    • 2
  • Hironori Yamasaki
    • 3
  • Masanori Ikeda
    • 4
  • Nobuyuki Kato
    • 4
  • Katsumi Eguchi
    • 2
  1. 1.Department of Clinical Pharmaceutics, Graduate School of Biomedical SciencesNagasaki UniversityNagasakiJapan
  2. 2.The First Department of Internal Medicine, Graduate School of Biomedical SciencesNagasaki UniversityNagasakiJapan
  3. 3.Health Research Center, Graduate School of Biomedical SciencesNagasaki UniversityNagasakiJapan
  4. 4.Department of Molecular Biology, Graduate School of Medicine and DentistryOkayama UniversityOkayamaJapan

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