Abstract
Macrophages are the principal source of TNFalpha, yet they are highly resistant to TNFalpha-mediated cell death. Previously, employing in vitro differentiated human macrophages, we showed that following the inhibition of NF-kappaB, TNFalpha-induced caspase-8 activation contributes to DNA fragmentation but is not necessary for the loss of the inner mitochondrial transmembrane potential (DeltaPsim) or cell death. We here extend these observations to demonstrate that, when NF-kappaB is inhibited in macrophages, TNFalpha alters lysosomal membrane permeability (LMP). This results in the release of cathepsin B with subsequent loss of DeltaPsim and caspase-8 independent cell death. Interestingly, the cytoprotective, NF-kappaB-dependent protein A20 was rapidly induced in macrophages treated with TNFalpha. Ectopic expression of A20 in macrophages preserves LMP following treatment with TNFalpha, and as a result, mitochondrial integrity is safeguarded and macrophages are protected from cell death. These observations demonstrate that TNFalpha triggers both caspase 8-dependent and -independent cell death pathways in macrophages and identify a novel mechanism by which A20 protects these cells against both pathways.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Apoptosis / drug effects
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Apoptosis / physiology*
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Caspase 8 / metabolism*
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Cathepsin B / metabolism
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Cell Survival / drug effects
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Cell Survival / physiology
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Cells, Cultured
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Cytochromes c / metabolism
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DNA Fragmentation / drug effects
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DNA-Binding Proteins
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Genetic Vectors / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins / drug effects
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Intracellular Signaling Peptides and Proteins / metabolism*
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Lysosomes / drug effects
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Lysosomes / metabolism
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Macrophages / drug effects
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Macrophages / metabolism*
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Membrane Potential, Mitochondrial / drug effects
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Membrane Potential, Mitochondrial / physiology
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Monocytes / drug effects
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Monocytes / metabolism*
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Nuclear Proteins / drug effects
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Nuclear Proteins / metabolism*
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Reactive Oxygen Species / metabolism
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Transfection
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Tumor Necrosis Factor alpha-Induced Protein 3
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Tumor Necrosis Factor-alpha / pharmacology
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Tumor Necrosis Factor-alpha / physiology*
Substances
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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NF-kappa B
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Nuclear Proteins
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Reactive Oxygen Species
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Tumor Necrosis Factor-alpha
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Cytochromes c
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TNFAIP3 protein, human
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Tumor Necrosis Factor alpha-Induced Protein 3
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Caspase 8
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Cathepsin B