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Cancer Immunology, Immunotherapy

, Volume 43, Issue 2, pp 109–115 | Cite as

Bcl-2 protects cells from cytokine-induced nitric-oxide-dependent apoptosis

  • Keping Xie
  • Suyun Huang
  • Yunfang Wang
  • Pedro J. Beltran
  • Shin-Hun Juang
  • Zhongyun Dong
  • John C. Reed
  • Timothy J. McDonnell
  • David J. McConkey
  • I. J. Fidler
ORIGINAL ARTICLE

Abstract

 Cytokine-mediated cell death in tumor cells can be achieved through endogenous nitric oxide (NO) from within tumor cells or exogenous NO from either activated macrophages or endothelial cells. The purpose of this study was to determine the role of Bcl-2 in NO-mediated apoptosis. The incubation of murine L929 and NIH3T3 cells with interleukin-1α (IL-1α) and interferon γ (IFNγ) induced high endogenous NO production only in the L929 cells that also underwent apoptosis. NIH3T3 cells were not resistant to NO-mediated apoptosis. In fact, the incubation of L929 and NIH3T3 cells with exogenous NO derived from NO donors, sodium nitroprusside, or S-nitroso-N-acetyl-DL-penicillamine (SNAP) induced death, characterized by typical apoptotic morphology and DNA fragmentation, in both cell types, but to a higher degree in NIH3T3 cells than in the L929 cells. We then measured the effect of Bcl-2 expression on exogenous NO-induced apoptosis. At both the mRNA and protein levels, L929 fibroblasts expressed higher levels of endogenous mouse Bcl-2 than did NIH3T3 cells. At the same time, L929 cells were much more resistant to exogenous NO-induced cell death than were NIH3T3 cells. The inverse correlation between mouse Bcl-2 expression and sensitivity to exogenous NO-mediated cell death was also found in the murine K-1735 melanoma C-23 and X-21 clonal populations. Transfection of both NIH3T3 cells and L929 cells with the human bcl-2 gene led to resistance to both exogenous and endogenous NO-mediated apoptosis. These data demonstrate that NO-mediated apoptosis can be suppressed by expression of Bcl-2, suggesting that abnormal expression of Bcl-2 may influence the efficacy of tumor immunotherapy.

Key words Cytokine Nitric oxide Bcl-2 Apoptosis Tumor 

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Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

  • Keping Xie
    • 1
  • Suyun Huang
    • 1
  • Yunfang Wang
    • 1
  • Pedro J. Beltran
    • 1
  • Shin-Hun Juang
    • 1
  • Zhongyun Dong
    • 1
  • John C. Reed
    • 3
  • Timothy J. McDonnell
    • 2
  • David J. McConkey
    • 1
  • I. J. Fidler
    • 1
  1. 1.Department of Cell Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USAUS
  2. 2.Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USAUS
  3. 3.The Burnham Institute, La Jolla, CA 92037, USAUS

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