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

• Published in: Journal of gastroenterology 2009-08, Vol.44 (8), p.856
• Main Authors: Matsumoto, Azusa, Ichikawa, Tatsuki, Nakao, Kazuhiko, Miyaaki, Hisamitsu, Hirano, Kumi, Fujimito, Masumi, Akiyama, Motohisa, Miuma, Satoshi, Ozawa, Eisuke, Shibata, Hidetaka, Takeshita, Shigeyuki, Yamasaki, Hironori, Ikeda, Masanori, Kato, Nobuyuki, Eguchi, Katsumi
• Format: Article
• Language: English
• ISSN: 0944-1174; 1435-5922
• DOI: 10.1007/s00535-009-0075-1

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. 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. 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.