TNF-α-Induced Apoptosis of Macrophages Following Inhibition of NF-κB: A Central Role for Disruption of Mitochondria

Hongtao Liu, Yingyu Ma, Lisa J. Pagliari, Harris Perlman, Chenfei Yu, Anning Lin, Richard M. Pope*

*Corresponding author for this work

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Previously, we established that suppressing the constitutive activation of NF-κB in in vitro matured human macrophages resulted in apoptosis initiated by a decrease of the Bcl-2 family member, A1, and the loss of mitochondrial transmembrane potential (Δψm). This study was performed to characterize the mechanism of TNF-α-induced apoptosis in macrophages following the inhibition of NF-κB. The addition of TNF-α markedly enhanced the loss of Δψm and the induction of apoptotic cell death. Although caspase 8 was activated and contributed to DNA fragmentation, it was not necessary for the TNF-α-induced loss of Δψm. The inhibition of NF-κB alone resulted in the release of cytochrome c from the mitochondria, while both cytochrome c and second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI were released following the addition of TNF-α. Furthermore, c-Jun N-terminal kinase activation, which was sustained following treatment with TNF-α when NF-κB was inhibited, contributed to DNA fragmentation. These observations demonstrate that cytochrome c and second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI may be differentially released from the mitochondria, and that the sustained activation of c-Jun N-terminal kinase modulated the DNA fragmentation independent of the loss of Δψm.

Original languageEnglish (US)
Pages (from-to)1907-1915
Number of pages9
JournalJournal of Immunology
Volume172
Issue number3
DOIs
StatePublished - Feb 1 2004

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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