, Volume 1, Issue 3, pp 209–212 | Cite as

Upregulation of Fas-induced apoptosis by interferon-γ accompanied by increased ICE expression in renal cell cancer cells

  • Y. Tomita
  • V. Bilim
  • M. Takeda
  • K. Takahashi


The integration of Fas/Apo-1 (CD95) by Fas ligand or anti-Fas antibody induces apoptosis, and this system plays a pivotal role for the lysis of target cells by cytotoxic T lymphocytes. Fas-mediated apoptosis is also increased by a prior incubation of Fas-bearing cells with interferon(IFN)-γ. Interleukin-1-β converting enzyme (ICE) and/or CPP32, or other members of ICE family act as direct cell death executors downstream of this mechanism, and a tetrapeptide inhibitor of these cysteine proteases blocks Fas-mediated apoptosis. In this study, we examined the effect of IFN-γ on Fas-mediated apoptosis in ACHN cells. IFN-γ augmented apoptosis in a dose dependent manner and reached a plateau at 400 U/ml when exposed for 48 h before the end of culture. The kinetics revealed a significant increase in apoptosis after 24 h. Exposing ACHN cells to IFN-γ increased pro-ICE expression accompanied with a decrease of pro-CPP32. These results suggest that direct enhancement of ICE expression and/or upregulation of conversion of pro-CPP32 to active form increases Fas-mediated apoptosis by IFN-γ in ACHN cells.

Key words

Apoptosis Fas interferon-γ renal cell cancer 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Ju ST, Panka DJ, Cui H,et al. Fas (CD95)/FasL interactions required for programmed cell death after T-cell activation.Nature 1995;373: 444–448.PubMedGoogle Scholar
  2. 2.
    Nagata S, Golstein P. The Fas death factor.Science 1995;267: 1449–1456.PubMedGoogle Scholar
  3. 3.
    Yonehara S, Ishii A, Yonehara M. A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor.J Exp Med 1989;169: 1747–1756.PubMedGoogle Scholar
  4. 4.
    Tamura T, Ishihara M, Lamphier MS,et al. An IRF-1-dependent pathway of DNA damage-induced apoptosis in mitogen-activated T lymphocytes.Nature 1995;376: 596–599.PubMedGoogle Scholar
  5. 5.
    Pine R, Canova A, Schindler C. Tyrosine phosphorylated p91 binds to a single element in the ISGF2/IRF-1 promoter to mediate induction by IFNα and IFNγ, and is likely to autoregulate the p91 gene.EMBO J 1994;13: 158–167.PubMedGoogle Scholar
  6. 6.
    Tomita Y, Kawasaki T, Bilim V, Takeda M, Takahashi K. Tetrapeptide DEVD-aldehyde or YVAD-chloromethylketone Inhibits Fas/Apo-1 (CD95)-mediated apoptosis in renal cell cancer cells.Int J Cancer 1996;68: 132–135.PubMedGoogle Scholar
  7. 7.
    Tomita Y, Bilim V, Kawasaki T,et al. Frequent expression of Bcl-2 in renal cell carcinomas carrying wild-type p53.Int J Cancer 1996;66: 322–325.PubMedGoogle Scholar
  8. 8.
    Williams MS, Henkart PA. Apoptotic cell death induced by intracellular proteolysis.J Immunol 1994; 153: 4247–4255.PubMedGoogle Scholar
  9. 9.
    Yagoda A. Chemotherapy of renal cell carcinoma: 1983–1989.Semin Urol 1989;7: 199–202.Google Scholar
  10. 10.
    Forman JD. The role of radiation therapy in the management of carcinoma of the kidney.Semin Urol 1989;7: 195–198.PubMedGoogle Scholar
  11. 11.
    Savage PD. Renal cell carcinoma.Curr Opin Oncol 1995;7: 275–280.PubMedGoogle Scholar
  12. 12.
    Montel AH, Bochan MR, Hobbs JA, Lynch DH, Brahmi Z. Fas involvement in cytotoxicity mediated by human NK cells.Cell Immunol 1995;166: 236–246.PubMedGoogle Scholar
  13. 13.
    Enari M, Hug H, Nagata S. Involvement of an ICE-like protease in Fas-mediated apoptosis.Nature 1995;375: 78–81.PubMedGoogle Scholar
  14. 14.
    Schlegel J, Peters I, Orrenius S,et al. CPP32/apopain is a key interleukin l β-converting enzyme-like protease involved in Fas-mediated apoptosis.J Biol Chem 1996;271: 1841–1844.PubMedGoogle Scholar
  15. 15.
    Nicholson DW, Ali A, Thornberry NA,et al. Identification and inhibition of the ICE/CPD-3 protease necessary for mammalian apoptosis.Nature 1995;376: 37–43.PubMedGoogle Scholar
  16. 16.
    Shresta S, Heusel JW, Macivor DM, Wesselschmidt RL, Russell JH, Ley TJ. Granzyme B plays a critical role in cytotoxic lymphocyte-induced apoptosis.Immunol Rev 1995;146: 211–221.PubMedGoogle Scholar
  17. 17.
    Darmon AJ, Nicholson DW, Bleackley RC. Activation of the apoptotic protease CPP32 by cytotoxic T-cell-derived granzyme B.Nature 1995;377: 446–468.PubMedGoogle Scholar
  18. 18.
    Lazebnik YA, Kaufmann SH, Desnoyers S, Poirier GG, Earnshaw WC. Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE.Nature 1994;371: 346–347.PubMedGoogle Scholar
  19. 19.
    Tewari M, Quan LT, O'Rourke K,et al. Yama/CPP32 β, a mammalian homolog of CED-3, is a CrmA-inhibitable pro tease that cleaves the death substrate poly(ADP-ribose) polymerase.Cell 1995;81: 801–809.PubMedGoogle Scholar
  20. 20.
    Li P, Allen H, Banerjee S,et al. Mice deficient in IL-1 β-converting enzyme are defective in production of mature IL-1 β and resistant to endotoxic shock.Cell 1995;80: 401–411.PubMedGoogle Scholar
  21. 21.
    Kuida K, Lippke JA, Ku G,et al. Altered cytokine export and apoptosis in mice deficient in interleukin-1 β converting enzyme.Science 1995;267: 2000–2003.PubMedGoogle Scholar

Copyright information

© Rapid Science Publishers 1996

Authors and Affiliations

  • Y. Tomita
    • 1
  • V. Bilim
    • 1
  • M. Takeda
    • 1
  • K. Takahashi
    • 1
  1. 1.Department of UrologyNiigata University School of MedicineNiigataJapan

Personalised recommendations