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-Induced Apoptosis of Macrophages Following Inhibition of NF-
B: A Central Role for Disruption of Mitochondria1
* Northwestern University Feinberg School of Medicine and Lakeside Division, Division of Rheumatology, Department of Medicine, Veterans Administration Medical Center, Chicago, IL 60611;
Integrated Graduate Program in the Life Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611; and
Ben May Institute for Cancer Research, University of Chicago, Chicago, IL 60637
Previously, we established that suppressing the constitutive activation of NF-
B 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 (
m). This study was performed to characterize the mechanism of TNF-
-induced apoptosis in macrophages following the inhibition of NF-B. The addition of TNF- markedly enhanced the loss of 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--induced loss of m. The inhibition of NF-B 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-. Furthermore, c-Jun N-terminal kinase activation, which was sustained following treatment with TNF- when NF-B 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 m.
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