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Molecular and Cellular Biology, December 2000, p. 8855-8865, Vol. 20, No. 23
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Macrophages Require Constitutive NF-kappa B Activation To Maintain A1 Expression and Mitochondrial Homeostasis

Lisa J. Pagliari,1,2 Harris Perlman,1 Hongtao Liu,1 and Richard M. Pope1,*

Division of Rheumatology, Department of Medicine,1 and Integrated Graduate Program in the Life Sciences,2 Northwestern University Medical School, Chicago, Illinois 60611

Received 29 August 2000/Accepted 5 September 2000

NF-kappa B 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-kappa B activation is essential for macrophage survival. Blocking the constitutive activation of NF-kappa B with pyrrolidine dithiocarbamate or expression of Ikappa Balpha 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-kappa B activation induced a time-dependent loss of mitochondrial transmembrane potential (Delta Psi 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 Delta Psi 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 Delta Psi m loss and that ectopic expression of A1 protected against cell death following inactivation of NF-kappa B. These data suggest that inhibition of NF-kappa B in macrophages initiates caspase 3-independent apoptosis through reduced A1 expression and mitochondrial dysfunction. Thus, constitutive NF-kappa B activation preserves macrophage viability by maintaining A1 expression and mitochondrial homeostasis.

* Corresponding author. Mailing address: Division of Rheumatology, Department of Medicine, Northwestern University Medical School and the Chicagoland Veterans Administration Medical Center, 303 E. Chicago Ave., Ward 3-315, Chicago, IL 60611. Phone: (312) 503-8003. Fax: (312) 503-0994. E-mail: RMP158{at}nwu.edu.

Molecular and Cellular Biology, December 2000, p. 8855-8865, Vol. 20, No. 23
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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