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TNFalpha-induced macrophage death via caspase-dependent and independent pathways

Tri M Tran1, Vladislav Temkin, Bo Shi

  • 1Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, 240 E. Huron Street, Chicago, IL 60611, USA.

Apoptosis : an International Journal on Programmed Cell Death
|January 20, 2009
PubMed

Insights

Tumor Necrosis Factor-alpha (TNFalpha) induces cell death in macrophages via lysosomal membrane permeability (LMP) and cathepsin B release when NF-kappaB is inhibited. The protein A20 protects macrophages from TNFalpha-induced death.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Macrophages are key producers of Tumor Necrosis Factor-alpha (TNFalpha).
  • Macrophages exhibit resistance to TNFalpha-mediated cell death.
  • Previous studies indicated NF-kappaB inhibition affects TNFalpha-induced caspase-8 activation and DNA fragmentation but not mitochondrial potential loss or cell death.

Purpose of the Study:

  • To investigate the mechanisms of TNFalpha-induced cell death in macrophages when NF-kappaB is inhibited.
  • To elucidate the role of lysosomal membrane permeability (LMP) and cathepsin B in this process.
  • To determine the protective role of the protein A20 against TNFalpha-induced macrophage death.

Main Methods:

  • In vitro differentiation of human macrophages.
  • Inhibition of NF-kappaB signaling pathway.
  • Assessment of TNFalpha-induced changes in lysosomal membrane permeability (LMP).
  • Measurement of mitochondrial transmembrane potential (DeltaPsim) and caspase-8 activation.
  • Analysis of cathepsin B release.
  • Evaluation of cell death pathways.
  • Ectopic expression of A20 in macrophages.

Main Results:

  • Inhibition of NF-kappaB in macrophages leads to TNFalpha-induced alteration of lysosomal membrane permeability (LMP).
  • TNFalpha triggers cathepsin B release, subsequent loss of mitochondrial transmembrane potential (DeltaPsim), and caspase-8 independent cell death.
  • The NF-kappaB-dependent protein A20 is rapidly induced by TNFalpha in macrophages.
  • Ectopic expression of A20 preserves LMP and mitochondrial integrity, protecting macrophages from TNFalpha-induced cell death.

Conclusions:

  • TNFalpha activates both caspase-8 dependent and independent cell death pathways in macrophages.
  • A20 plays a novel protective role by maintaining lysosomal membrane permeability and mitochondrial integrity, thereby preventing TNFalpha-induced macrophage death.

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