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

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23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)856-863
Number of pages8
JournalJournal of Gastroenterology
Volume44
Issue number8
DOIs
Publication statusPublished - May 13 2009

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Keywords

  • HCV
  • Interferon
  • PKR
  • STAT-1
  • mTOR

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Matsumoto, A., Ichikawa, T., Nakao, K., Miyaaki, H., Hirano, K., Fujimito, M., Akiyama, M., Miuma, S., Ozawa, E., Shibata, H., Takeshita, S., Yamasaki, H., Ikeda, M., Kato, N., & Eguchi, K. (2009). Interferon-α-induced mTOR activation is an anti-hepatitis C virus signal via the phosphatidylinositol 3-kinase-Akt-independent pathway. Journal of Gastroenterology, 44(8), 856-863. https://doi.org/10.1007/s00535-009-0075-1