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

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Title: Interferon-alpha-induced mTOR activation is an anti-hepatitis C virus signal via the phosphatidylinositol 3-kinase-Akt-independent pathway.
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
Issue Date: May-2009
Publisher: Springer Japan
Citation: Journal of Gastroenterology, 44(8), pp.856-863; 2009
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-alpha, tyrosine phosphorylation of STAT-1 was diminished. Pretreatment of rapa had an inhibitory effect on the IFN-alpha-induced expression of PKR and p48 in a dose dependent manner. Rapa inhibited the IFN-alpha inducible IFN-stimulated regulatory element luciferase activity in a dose-dependent manner. However, wortmannin, LY294002 and Akt inhibitor did not influence IFN-alpha inducible luciferase activity. To examine the effect of PI3-K-Akt-mTOR on the anti-HCV action of IFN-alpha, the full-length HCV replication system, OR6 cells were used. The pretreatment of rapa attenuated its anti-HCV replication effect in comparison to IFN-alpha 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
URI: http://hdl.handle.net/10069/23195
ISSN: 09441174
DOI: 10.1007/s00535-009-0075-1
PubMed ID: 19436942
Rights: © Springer 2009 / The original publication is available at www.springerlink.com
Type: Journal Article
Text Version: author
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/23195

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