NF-κB protects macrophages from lipopolysaccharide-induced cell death: The role of caspase 8 and receptor-interacting protein

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-κB activation promotes resistance to cell death in macrophages. When NF-κB activation was inhibited by a super-repressor, IκBα, the TLR4 ligand lipopolysaccharide induced the activation of caspase 8, the loss of mitochondrial transmembrane potential (Δψ_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 Δψ_m and resulted in necrotic cell death. In contrast, the reduction of receptor-interacting protein 1 suppressed the loss of Δψ_m and inhibited apoptotic cell death. Further, when caspase 8 activation was suppressed, the knock down of receptor-interacting protein inhibited the loss of Δψ_m and necrotic cell death. These observations demonstrate that following TLR4 ligation by lipopolysaccharide, NF-κB is a critical determinant of macrophage life or death, whereas caspase 8 determines the pathway employed.