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Published on: June 29, 2011

Cytokine-induced apoptosis in transformed murine fibroblasts involves synthesis of endogenous nitric-oxide

K Xie1, S Huang, Z Dong

  • 1UNIV TEXAS,MD ANDERSON CANC CTR,DEPT CELL BIOL,HMB 173,1515 HOLCOMBE BLVD,HOUSTON,TX 77030.

International Journal of Oncology
|May 17, 2011
PubMed

Insights

This study shows that endogenous nitric oxide (NO) plays a key role in cytokine-induced apoptosis of transformed fibroblasts. Inhibiting nitric oxide synthase significantly reduced cell death and DNA fragmentation.

Area of Science:

  • Cell Biology
  • Immunology
  • Biochemistry

Background:

  • Apoptosis, or programmed cell death, is crucial for normal development and tissue homeostasis.
  • Tumor necrosis factor-alpha (TNF-alpha) and other cytokines can induce apoptosis in various cell types.
  • The precise mechanisms underlying cytokine-induced apoptosis in transformed cells are not fully understood.

Purpose of the Study:

  • To investigate the role of endogenous nitric oxide (NO) synthesis in the apoptosis of murine L929 transformed fibroblasts.
  • To determine if NO production is a critical mediator in TNF-alpha, interleukin-1, and lipopolysaccharide (LPS)-induced cell death.

Main Methods:

  • Murine L929 fibroblasts (parental and TNF-alpha-resistant) were cultured in vitro.
  • Cells were treated with TNF-alpha, interleukin-1, and LPS, with or without mouse interferon-gamma (IFN-gamma).
  • Nitric oxide production was measured, and cell death was assessed via DNA fragmentation assays. N(G)-methyl-L-arginine (NMA), a nitric oxide synthase inhibitor, was used to block NO synthesis.

Main Results:

  • Combining subthreshold concentrations of IFN-gamma with cytokines or LPS induced significant cell death within 48 hours.
  • This cell death was accompanied by increased nitric oxide (NO) production.
  • The addition of NMA significantly inhibited both cell death and NO production.
  • NMA also suppressed the observed internucleosomal DNA fragmentation, a hallmark of apoptosis.

Conclusions:

  • Endogenous nitric oxide (NO) synthesis is critically involved in cytokine- and LPS-induced apoptosis of murine L929 transformed fibroblasts.
  • NO acts as a mediator in the synergistic cytotoxic effects of IFN-gamma combined with other inflammatory stimuli.
  • Targeting NO production may represent a therapeutic strategy for modulating apoptosis in certain transformed cell types.

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