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

Tri M. Tran, Vladislav Temkin, Bo Shi, Lisa Pagliari, Soizic Daniel, Christiane Ferran, Richard M. Pope

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Macrophages are the principal source of TNFα, yet they are highly resistant to TNFα-mediated cell death. Previously, employing in vitro differentiated human macrophages, we showed that following the inhibition of NF-κB, TNFα-induced caspase-8 activation contributes to DNA fragmentation but is not necessary for the loss of the inner mitochondrial transmembrane potential (ΔΨm) or cell death. We here extend these observations to demonstrate that, when NF-κB is inhibited in macrophages, TNFα alters lysosomal membrane permeability (LMP). This results in the release of cathepsin B with subsequent loss of ΔΨm and caspase-8 independent cell death. Interestingly, the cytoprotective, NF-κB-dependent protein A20 was rapidly induced in macrophages treated with TNFα. Ectopic expression of A20 in macrophages preserves LMP following treatment with TNFα, and as a result, mitochondrial integrity is safeguarded and macrophages are protected from cell death. These observations demonstrate that TNFα triggers both caspase 8-dependent and -independent cell death pathways in macrophages and identify a novel mechanism by which A20 protects these cells against both pathways.

Original languageEnglish (US)
Pages (from-to)320-332
Number of pages13
JournalApoptosis
Volume14
Issue number3
DOIs
StatePublished - Mar 2009

Keywords

  • A20
  • Apoptosis
  • Caspase-8
  • Cathepsin B

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Cancer Research

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