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Involvement of TWEAK in interferon gamma-stimulated monocyte cytotoxicity

M Nakayama1, N Kayagaki, N Yamaguchi

  • 1Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.

The Journal of Experimental Medicine
|November 9, 2000
PubMed

Insights

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is expressed on monocytes stimulated by interferon-gamma, enhancing their ability to kill tumor cells. This reveals a new pathway for monocyte-mediated cancer cell death.

Area of Science:

  • Immunology
  • Cell Biology
  • Cancer Research

Background:

  • Tumor necrosis factor (TNF) family member TWEAK has unknown physiological roles.
  • TWEAK can induce cell death in certain tumor cell lines.

Purpose of the Study:

  • Investigate TWEAK expression and function in human peripheral blood mononuclear cells (PBMCs).
  • Characterize the role of TWEAK in monocyte-mediated cytotoxicity against tumor cells.

Main Methods:

  • Generated novel anti-human TWEAK monoclonal antibodies (mAbs).
  • Analyzed TWEAK expression on PBMCs stimulated with various cytokines (IFN-gamma, IFN-alpha) and lipopolysaccharide.
  • Assessed monocyte cytotoxic activity against HSC3 squamous carcinoma cells using anti-TWEAK and anti-TRAIL mAbs.

Main Results:

  • Fresh PBMCs showed no detectable surface TWEAK.
  • Monocyte TWEAK expression was rapidly induced by interferon-gamma, but not IFN-alpha or LPS.
  • IFN-gamma-stimulated monocyte cytotoxicity against HSC3 cells was partially inhibited by anti-TWEAK mAb and significantly by combined anti-TWEAK and anti-TRAIL mAbs.

Conclusions:

  • Reveals a novel TWEAK-mediated pathway for monocyte cytotoxicity against tumor cells.
  • Interferon-gamma potentiates this TWEAK-dependent anti-tumor activity.
  • This finding has implications for understanding immune responses in cancer.

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