NF-kappaB 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-kappaB activation promotes resistance to cell death in macrophages. When NF-kappaB activation was inhibited by a super-repressor, IkappaBalpha, the TLR4 ligand lipopolysaccharide induced the activation of caspase 8, the loss of mitochondrial transmembrane potential (DeltaPsim), and apoptotic cell death in macrophages. The inhibition of caspase 8 activation suppressed DNA fragmentation but failed to protect macrophages against the loss of DeltaPsim and resulted in necrotic cell death. In contrast, the reduction of receptor-interacting protein 1 suppressed the loss of DeltaPsim and inhibited apoptotic cell death. Further, when caspase 8 activation was suppressed, the knock down of receptor-interacting protein inhibited the loss of DeltaPsim and necrotic cell death. These observations demonstrate that following TLR4 ligation by lipopolysaccharide, NF-kappaB is a critical determinant of macrophage life or death, whereas caspase 8 determines the pathway employed.
Ma
Yingyu
Y
Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine and the Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60611, USA.
Temkin
Vladislav
V
Liu
Hongtao
H
Pope
Richard M
RM
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000648:ultrastructure; D008564:Membrane Potentials; D008854:Microscopy, Electron; D016328:NF-kappa B / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D051197:Toll-Like Receptor 4 / Q000502:physiology; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism*
D008070:Lipopolysaccharides; D016328:NF-kappa B; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases