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


RESULTS
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.


CONCLUSIONS
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.
Department of Clinical Pharmaceutics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
Azusa
A
Matsumoto
Tatsuki
T
Ichikawa
Kazuhiko
K
Nakao
Hisamitsu
H
Miyaaki
Kumi
K
Hirano
Masumi
M
Fujimito
Motohisa
M
Akiyama
Satoshi
S
Miuma
Eisuke
E
Ozawa
Hidetaka
H
Shibata
Shigeyuki
S
Takeshita
Hironori
H
Yamasaki
Masanori
M
Ikeda
Nobuyuki
N
Kato
Katsumi
K
Eguchi
D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D016174:Hepacivirus / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D053612:Janus Kinases; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D019892:eIF-2 Kinase; C546842:MTOR protein, human