Abstract
TNF-related apoptosis-inducing ligand (TRAIL) is able to kill many transformed cells of diverse tissue types. We show that TRAIL is inducible by IFN-gamma, by TNF-alpha, and by infection with human CMV, and has potent antiviral activity in vitro. CMV infection and IFN-gamma also reciprocally modulate TRAIL receptor (TRAIL-R) expression. CMV infection increased the expression of TRAIL-R1 and -R2, whereas IFN-gamma down-regulated the expression of TRAIL-Rs on uninfected fibroblasts. Moreover, IFN-gamma significantly decreased the basal level of NF-kappaB activation, a known survival factor that inhibits apoptosis. Thus, TRAIL selectively kills virus-infected cells while leaving uninfected cells intact, and IFN-gamma potentiates these effects by dynamic modulation of TRAIL and TRAIL-R expression and by sensitizing cells to apoptosis. The regulation of TRAIL and TRAIL-R expression may represent a general mechanism that contributes to the control of TRAIL-mediated apoptosis.
MeSH terms
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Adjuvants, Immunologic / pharmacology*
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Antiviral Agents / pharmacology*
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Apoptosis Regulatory Proteins
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Cell Death / immunology
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Cells, Cultured
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Cytokines / physiology
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Cytomegalovirus / immunology
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Cytomegalovirus / physiology
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Drug Synergism
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Fibroblasts
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Humans
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Interferon-gamma / physiology*
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Membrane Glycoproteins / biosynthesis*
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology
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NF-kappa B / metabolism
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RNA, Messenger / biosynthesis
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Receptors, Tumor Necrosis Factor / biosynthesis*
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Receptors, Tumor Necrosis Factor / genetics
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Necrosis Factor-alpha / biosynthesis*
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / physiology
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Virus Replication / immunology
Substances
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Adjuvants, Immunologic
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Antiviral Agents
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Apoptosis Regulatory Proteins
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Cytokines
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Membrane Glycoproteins
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NF-kappa B
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RNA, Messenger
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Receptors, Tumor Necrosis Factor
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tumor Necrosis Factor-alpha
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Interferon-gamma