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J. Biol. Chem., Vol. 280, Issue 51, 41827-41834, December 23, 2005

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NF-B Protects Macrophages from Lipopolysaccharide-induced Cell Death

THE ROLE OF CASPASE 8 AND RECEPTOR-INTERACTING PROTEIN^*

From the Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine and the Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60611

Macrophages play a pivotal role in the pathogenesis of a variety of diseases. These studies were performed to characterize the mechanisms by which Toll-like receptor 4 (TLR4)-mediated NF-B activation promotes resistance to cell death in macrophages. When NF-B activation was inhibited by a super-repressor, IB, the TLR4 ligand lipopolysaccharide induced the activation of caspase 8, the loss of mitochondrial transmembrane potential (_m), and apoptotic cell death in macrophages. The inhibition of caspase 8 activation suppressed DNA fragmentation but failed to protect macrophages against the loss of _m and resulted in necrotic cell death. In contrast, the reduction of receptor-interacting protein 1 suppressed the loss of _m and inhibited apoptotic cell death. Further, when caspase 8 activation was suppressed, the knock down of receptor-interacting protein inhibited the loss of _m and necrotic cell death. These observations demonstrate that following TLR4 ligation by lipopolysaccharide, NF-B is a critical determinant of macrophage life or death, whereas caspase 8 determines the pathway employed.

Received for publication, October 5, 2005

^* This work was supported by National Institutes of Health Grants R01AR049217 and R01AR048269 (to R. M. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Division of Rheumatology, Dept. of Medicine, Northwestern University Feinberg School of Medicine, 240 E. Huron St., Suite M300, Chicago, IL 60611. Tel.: 312-503-8003; Fax: 312-503-0994; E-mail: rmp158{at}northwestern.edu.

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