Abstract
TRAIL receptor (TRAIL-R) signaling has been implicated in inducing apoptosis in tumor cells, but little is understood about its physiological function. Here, we report the generation and characterization of TRAIL-R(-/-) mice, which develop normal lymphocyte populations but possess enhanced innate immune responses. TRAIL-R(-/-) mice exhibited increased clearance of murine cytomegalovirus that correlated with increased levels of IL-12, IFN-alpha, and IFN-gamma. Stimulation of macrophages with Mycobacterium and Toll-like receptor (TLR)-2, -3, and -4, but not TLR9, ligands resulted in high levels of TRAIL upregulation and enhanced cytokine production in TRAIL-R(-/-) cells. The immediate-early TLR signaling events in TRAIL-R(-/-) macrophages and dendritic cells are normal, but I kappa B-alpha homeostatic regulation and NF-kappa B activity at later time points is perturbed. These data suggest that TRAIL-R negatively regulates innate immune responses.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Apoptosis Regulatory Proteins
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Base Sequence
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Cytokines / biosynthesis
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Cytokines / metabolism
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Gene Deletion
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Herpesviridae Infections / immunology
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Herpesviridae Infections / virology
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Immunity, Innate / immunology*
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Ligands
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Lipopolysaccharides / pharmacology
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Macrophages / immunology
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Macrophages / metabolism
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Knockout
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Molecular Sequence Data
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Muromegalovirus / immunology
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Mycobacterium bovis / immunology
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Receptors, Cell Surface / metabolism
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor / chemistry
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / metabolism*
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Signal Transduction
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T-Lymphocytes / cytology
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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T-Lymphocytes / virology
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TNF-Related Apoptosis-Inducing Ligand
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Time Factors
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Toll-Like Receptor 2
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Apoptosis Regulatory Proteins
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Cytokines
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Ligands
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Lipopolysaccharides
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Membrane Glycoproteins
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Receptors, Cell Surface
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor
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TNF-Related Apoptosis-Inducing Ligand
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Tnfrsf10b protein, mouse
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Tnfsf10 protein, mouse
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Toll-Like Receptor 2
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha