TY - JOUR
T1 - TNF-α-Induced Apoptosis of Macrophages Following Inhibition of NF-κB
T2 - A Central Role for Disruption of Mitochondria
AU - Liu, Hongtao
AU - Ma, Yingyu
AU - Pagliari, Lisa J.
AU - Perlman, Harris
AU - Yu, Chenfei
AU - Lin, Anning
AU - Pope, Richard M.
PY - 2004/2/1
Y1 - 2004/2/1
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.172.3.1907
DO - 10.4049/jimmunol.172.3.1907
M3 - Article
C2 - 14734776
AN - SCOPUS:1642566525
SN - 0022-1767
VL - 172
SP - 1907
EP - 1915
JO - Journal of Immunology
JF - Journal of Immunology
IS - 3
ER -