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.
雑誌名
Journal of Gastroenterology
巻
44
号
8
ページ
856 - 863
発行年
2009-05
出版者
Springer Japan
ISSN
09441174
EISSN
14355922
PubMed番号
19436942
DOI
10.1007/s00535-009-0075-1
権利
c Springer 2009
The original publication is available at www.springerlink.com
著者版フラグ
author
引用
Journal of Gastroenterology, 44(8), pp.856-863; 2009
Interferon-alpha-induced mTOR activation is an anti-hepatitis C virus signal via the phosphatidylinositol 3-kinase-Akt-independent pathway.
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