Affiliation:
1. Division of Rheumatology, Department of Medicine, 1 and
2. Integrated Graduate Program in the Life Sciences, 2 Northwestern University Medical School, Chicago, Illinois 60611
Abstract
ABSTRACT
NF-κB is a critical mediator of macrophage inflammatory responses, but its role in regulating macrophage survival has yet to be elucidated. Here, we demonstrate that constitutive NF-κB activation is essential for macrophage survival. Blocking the constitutive activation of NF-κB with pyrrolidine dithiocarbamate or expression of IκBα induced apoptosis in macrophagelike RAW 264.7 cells and primary human macrophages. This apoptosis was independent of additional death-inducing stimuli, including Fas ligation. Suppression of NF-κB activation induced a time-dependent loss of mitochondrial transmembrane potential (ΔΨ
m
) and DNA fragmentation. Examination of initiator caspases revealed the cleavage of caspase 9 but not caspase 8 or the effector caspase 3. Addition of a general caspase inhibitor, z-VAD.fmk, or a specific caspase 9 inhibitor reduced DNA fragmentation but had no effect on ΔΨ
m
collapse, indicating this event was caspase independent. To determine the pathway leading to mitochondrial dysfunction, analysis of Bcl-2 family members established that only A1 mRNA levels were reduced prior to ΔΨ
m
loss and that ectopic expression of A1 protected against cell death following inactivation of NF-κB. These data suggest that inhibition of NF-κB in macrophages initiates caspase 3-independent apoptosis through reduced A1 expression and mitochondrial dysfunction. Thus, constitutive NF-κB activation preserves macrophage viability by maintaining A1 expression and mitochondrial homeostasis.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
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