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Gliotoxin induces apoptosis in macrophages unrelated to its antiphagocytic properties

P Waring1, R D Eichner, A Müllbacher

  • 1Division of Virology and Cellular Pathology, John Curtin School of Medical Research, Australian National University, Canberra.

The Journal of Biological Chemistry
|December 5, 1988
PubMed

Insights

Gliotoxin causes programmed cell death (apoptosis) in macrophages by fragmenting DNA into specific sizes. This DNA damage mechanism is linked to the epipolythiodioxopiperazine (ETP) structure, not reactive oxygen species alone.

Area of Science:

  • Molecular Biology
  • Immunology
  • Toxicology

Background:

  • The fungal metabolite gliotoxin is an immunomodulating agent with known DNA-damaging capabilities.
  • Previous studies showed gliotoxin causes DNA fragmentation in cells and scission in plasmid DNA, potentially via reactive oxygen species (ROS).
  • The precise mechanism of genomic DNA damage by gliotoxin remained unclear.

Purpose of the Study:

  • To elucidate the mechanism by which gliotoxin and its analogues induce DNA damage in macrophages.
  • To investigate the role of specific structural features of gliotoxin in DNA fragmentation and apoptosis.
  • To determine if gliotoxin's effect on macrophage function is related to DNA damage.

Main Methods:

  • Treatment of macrophages with gliotoxin and structural analogues.
  • Analysis of DNA fragmentation patterns using gel electrophoresis.
  • Assessment of macrophage phagocytosis and adherence.
  • Evaluation of reactive oxygen species generation.

Main Results:

  • Gliotoxin and its analogues induced discrete DNA fragments (170 +/- 30 base pairs) in macrophages, characteristic of apoptosis.
  • Compounds with the epipolythiodioxopiperazine (ETP) bridged disulfide structure were equipotent in inducing DNA damage and affecting phagocytosis.
  • DNA damage was observed even when ROS generation was not the primary mechanism, suggesting an alternative pathway.
  • Gliotoxin's effect on macrophage adherence was independent of DNA damage.

Conclusions:

  • Gliotoxin induces apoptosis in macrophages via a specific DNA fragmentation pattern.
  • The epipolythiodioxopiperazine (ETP) structure is crucial for gliotoxin's DNA-damaging and immunomodulatory effects.
  • A novel mechanism of cell damage by gliotoxin and related ETP compounds, distinct from ROS, is suggested.

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