title: TNF-alpha-induced apoptosis of macrophages following inhibition of NF-kappa B: a central role for disruption of mitochondria.
abstract: Previously, we established that suppressing the constitutive activation of NF-kappaB 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 (Deltapsi(m)). This study was performed to characterize the mechanism of TNF-alpha-induced apoptosis in macrophages following the inhibition of NF-kappaB. The addition of TNF-alpha markedly enhanced the loss of Deltapsi(m) and the induction of apoptotic cell death. Although caspase 8 was activated and contributed to DNA fragmentation, it was not necessary for the TNF-alpha-induced loss of Deltapsi(m). The inhibition of NF-kappaB 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-alpha. Furthermore, c-Jun N-terminal kinase activation, which was sustained following treatment with TNF-alpha when NF-kappaB 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 Deltapsi(m).
authors.affiliation: Northwestern University Feinberg School of Medicine and Lakeside Division, Division of Rheumatology, Department of Medicine, Veterans Administration Medical Center, Chicago, IL 60611, USA.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Liu
authors.forename: Yingyu
authors.initials: Y
authors.lastname: Ma
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Pagliari
authors.forename: Harris
authors.initials: H
authors.lastname: Perlman
authors.forename: Chenfei
authors.initials: C
authors.lastname: Yu
authors.forename: Anning
authors.initials: A
authors.lastname: Lin
authors.forename: Richard M
authors.initials: RM
authors.lastname: Pope
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D015938:Complement Membrane Attack Complex; D003165:Complement System Proteins; D004789:Enzyme Activation / Q000276:immunology; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D008264:Macrophages / Q000166:cytology* / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D008564:Membrane Potentials / Q000276:immunology; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000276:Adjuvants, Immunologic; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D015938:Complement Membrane Attack Complex; C412403:DIABLO protein, human; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; C047610:SC5b-9 protein complex; D014409:Tumor Necrosis Factor-alpha; D003165:Complement System Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases