Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

IFN:

Interferon

HCV:

Hepatitis C virus

STAT:

Signal transducers and activators of transcription

ISGF-3:

IFN-stimulated gene factor 3

ISRE:

IFN-stimulated regulatory element

PKR:

Double-stranded RNA-dependent protein kinase

Rapa:

Rapamycin

PI3-K:

Phosphatidylinositol 3-kinase

mTOR:

Mammalian target of rapamycin

siRNA:

Small interfering RNA

References

  1. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127:S35–50.

    Article  PubMed  Google Scholar 

  2. Pawlotsky JM, Chevaliez S, McHutchison JG. The hepatitis C virus life cycle as a target for new antiviral therapies. Gastroenterology. 2007;132:1979–98.

    Article  PubMed  CAS  Google Scholar 

  3. Persico M, Capasso M, Persico E, Svelto M, Russo R, Spano D, et al. Suppressor of cytokine signaling 3 (SOCS3) expression and hepatitis C virus-related chronic hepatitis: insulin resistance and response to antiviral therapy. Hepatology. 2007;46:1009–15.

    Article  PubMed  CAS  Google Scholar 

  4. Walsh MJ, Jonsson JR, Richardson MM, Lipka GM, Purdie DM, Clouston AD, et al. Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signaling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1. Gut. 2006;55:529–35.

    Article  PubMed  CAS  Google Scholar 

  5. Huang Y, Feld JJ, Sapp RK, Nanda S, Lin JH, Blatt LM, et al. Defective hepatic response to interferon and activation of suppressor of cytokine signaling 3 in chronic hepatitis C. Gastroenterology. 2007;132:733–44.

    Article  PubMed  CAS  Google Scholar 

  6. Taylor MW, Tsukahara T, Brodsky L, Schaley J, Sanda C, Stephens MJ, et al. Changes in gene expression during pegylated interferon and ribavirin therapy of chronic hepatitis C virus distinguish responders from nonresponders to antiviral therapy. J Virol. 2007;81:3391–401.

    Article  PubMed  CAS  Google Scholar 

  7. Lan KH, Lan KL, Lee WP, Sheu ML, Chen MY, Lee YL, et al. HCV NS5A inhibits interferon-alpha signaling through suppression of STAT1 phosphorylation in hepatocyte-derived cell lines. J Hepatol. 2007;46:759–67.

    Article  PubMed  CAS  Google Scholar 

  8. van Boxel-Dezaire AH, Rani MR, Stark GR. Complex modulation of cell type-specific signaling in response to type I interferons. Immunity. 2006;25:361–72.

    Article  PubMed  Google Scholar 

  9. Ichikawa T, Nakao K, Nakata K, Yamashita M, Hamasaki K, Shigeno M, et al. Involvement of IL-1beta and IL-10 in IFN-alpha-mediated antiviral gene induction in human hepatoma cells. Biochem Biophys Res Commun. 2002;294:414–22.

    Article  PubMed  CAS  Google Scholar 

  10. Kaur S, Uddin S, Platanias LC. The PI3’ kinase pathway in interferon signaling. J Interferon Cytokine Res. 2005;25:780–7.

    Article  PubMed  CAS  Google Scholar 

  11. Kaur S, Lal L, Sassano A, Majchrzak-Kita B, Srikanth M, Baker DP, et al. Regulatory effects of mammalian target of rapamycin-activated pathways in type I and II interferon signaling. J Biol Chem. 2007;282:1757–68.

    Article  PubMed  CAS  Google Scholar 

  12. Kudchodkar SB, Del Prete GQ, Maguire TG, Alwine JC. AMPK-mediated inhibition of mTOR kinase is circumvented during immediate-early times of human cytomegalovirus infection. J Virol. 2007;81:3649–51.

    Article  PubMed  CAS  Google Scholar 

  13. Minami K, Tambe Y, Watanabe R, Isono T, Haneda M, Isobe K, et al. Suppression of viral replication by stress-inducible GADD34 protein via the mammalian serine/threonine protein kinase mTOR pathway. J Virol. 2007;81:11106–15.

    Article  PubMed  CAS  Google Scholar 

  14. Ishida H, Li K, Yi M, Lemon SM. p21-activated kinase 1 is activated through the mammalian target of rapamycin/p70 S6 kinase pathway and regulates the replication of hepatitis C virus in human hepatoma cells. J Biol Chem. 2007;282:11836–48.

    Article  PubMed  CAS  Google Scholar 

  15. Guo H, Zhou T, Jiang D, Cuconati A, Xiao GH, Block TM, et al. Regulation of hepatitis B virus replication by the phosphatidylinositol 3-kinase-Akt signal transduction pathway. J Virol. 2007;81:10072–80.

    Article  PubMed  CAS  Google Scholar 

  16. Mannova P, Beretta L. Activation of the N-Ras-PI3K-Akt-mTOR pathway by hepatitis C virus: control of cell survival and viral replication. J Virol. 2005;79:8742–9.

    Article  PubMed  CAS  Google Scholar 

  17. Nishimura D, Ishikawa H, Matsumoto K, Shibata H, Motoyoshi Y, Fukuta M, et al. DHMEQ, a novel NF-kappaB inhibitor, induces apoptosis and cell-cycle arrest in human hepatoma cells. Int J Oncol. 2006;29:713–9.

    PubMed  CAS  Google Scholar 

  18. Ikeda M, Abe K, Dansako H, Nakamura T, Naka K, Kato N. Efficient replication of a full-length hepatitis C virus genome, strain O, in cell culture, and development of a luciferase reporter system. Biochem Biophys Res Commun. 2005;329:1350–9.

    Article  PubMed  CAS  Google Scholar 

  19. Obora A, Shiratori Y, Okuno M, Adachi S, Takano Y, Matsushima-Nishiwaki R, et al. Synergistic induction of apoptosis by acyclic retinoid and interferon-beta in human hepatocellular carcinoma cells. Hepatology. 2002;36:1115–24.

    Article  PubMed  CAS  Google Scholar 

  20. Wang C, Pflugheber J, Sumpter R Jr, Sodora DL, Hui D, Sen GC, et al. Alpha interferon induces distinct translational control programs to suppress hepatitis C virus RNA replication. J Virol. 2003;77:3898–912.

    Article  PubMed  CAS  Google Scholar 

  21. Liu WL, Su WC, Cheng CW, Hwang LH, Wang CC, Chen HL, et al. Ribavirin up-regulates the activity of double-stranded RNA-activated protein kinase and enhances the action of interferon-alpha against hepatitis C virus. J Infect Dis. 2007;196:425–34.

    Article  PubMed  CAS  Google Scholar 

  22. Tamada Y, Nakao K, Nagayama Y, Nakata K, Ichikawa T, Kawamata Y, et al. p48 Overexpression enhances interferon-mediated expression and activity of double-stranded RNA-dependent protein kinase in human hepatoma cells. J Hepatol. 2002;37:493–9.

    Article  PubMed  CAS  Google Scholar 

  23. Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res. 2007;67:10804–12.

    Article  PubMed  CAS  Google Scholar 

  24. Mamane Y, Petroulakis E, LeBacquer O, Sonenberg N. mTOR, translation initiation and cancer. Oncogene. 2006;25:6416–22.

    Article  PubMed  CAS  Google Scholar 

  25. Hanada M, Feng J, Hemmings BA. Structure, regulation and function of PKB/AKT–a major therapeutic target. Biochim Biophys Acta. 2004;1697:3–16.

    PubMed  CAS  Google Scholar 

  26. Hresko RC, Mueckler M. mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3–L1 adipocytes. J Biol Chem. 2005;280:40406–16.

    Article  PubMed  CAS  Google Scholar 

  27. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7:606–19.

    Article  PubMed  CAS  Google Scholar 

  28. Molnarfi N, Hyka-Nouspikel N, Gruaz L, Dayer JM, Burger D. The production of IL-1 receptor antagonist in IFN-beta-stimulated human monocytes depends on the activation of phosphatidylinositol 3-kinase but not of STAT1. J Immunol. 2005;174:2974–80.

    PubMed  CAS  Google Scholar 

  29. Parmar S, Smith J, Sassano A, Uddin S, Katsoulidis E, Majchrzak B, et al. Differential regulation of the p70 S6 kinase pathway by interferon alpha (IFNalpha) and imatinib mesylate (STI571) in chronic myelogenous leukemia cells. Blood. 2005;106:2436–43.

    Article  PubMed  CAS  Google Scholar 

  30. Nguyen H, Ramana CV, Bayes J, Stark GR. Roles of phosphatidylinositol 3-kinase in interferon-gamma-dependent phosphorylation of STAT1 on serine 727 and activation of gene expression. J Biol Chem. 2001;276:33361–8.

    Article  PubMed  CAS  Google Scholar 

  31. Fang P, Hwa V, Rosenfeld RG. Interferon-gamma-induced dephosphorylation of STAT3 and apoptosis are dependent on the mTOR pathway. Exp Cell Res. 2006;312:1229–39.

    Article  PubMed  CAS  Google Scholar 

  32. El-Hashemite N, Zhang H, Walker V, Hoffmeister KM, Kwiatkowski DJ. Perturbed IFN-gamma-Jak-signal transducers and activators of transcription signaling in tuberous sclerosis mouse models: synergistic effects of rapamycin-IFN-gamma treatment. Cancer Res. 2004;64:3436–43.

    Article  PubMed  CAS  Google Scholar 

  33. Matsumoto K, Okano J, Murawaki Y. Differential effects of interferon alpha-2b and beta on the signaling pathways in human liver cancer cells. J Gastroenterol. 2005;40:722–32.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Pharmaceutics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan

    Azusa Matsumoto & Kumi Hirano

  2. The First Department of Internal Medicine, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan

    Tatsuki Ichikawa, Kazuhiko Nakao, Hisamitsu Miyaaki, Masumi Fujimito, Motohisa Akiyama, Satoshi Miuma, Eisuke Ozawa, Hidetaka Shibata, Shigeyuki Takeshita & Katsumi Eguchi

  3. Health Research Center, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan

    Hironori Yamasaki

  4. Department of Molecular Biology, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan

    Masanori Ikeda & Nobuyuki Kato

Authors
  1. Azusa Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tatsuki Ichikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kazuhiko Nakao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hisamitsu Miyaaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kumi Hirano
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masumi Fujimito
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Motohisa Akiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Satoshi Miuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Eisuke Ozawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hidetaka Shibata
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Shigeyuki Takeshita
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hironori Yamasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Masanori Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Nobuyuki Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Katsumi Eguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tatsuki Ichikawa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Matsumoto, A., Ichikawa, T., Nakao, K. et al. Interferon-α-induced mTOR activation is an anti-hepatitis C virus signal via the phosphatidylinositol 3-kinase-Akt-independent pathway. J Gastroenterol 44, 856–863 (2009). https://doi.org/10.1007/s00535-009-0075-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-009-0075-1

Keywords

Search

Navigation