title: TRAIL-R as a negative regulator of innate immune cell responses.
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.
authors.affiliation: Department of Molecular and Cell Biology, Division of Immunology and Cancer Research Laboratory, University of California, Berkeley, CA 94720, USA.
authors.forename: Gretchen E
authors.initials: GE
authors.lastname: Diehl
authors.forename: Herman H
authors.initials: HH
authors.lastname: Yue
authors.forename: Kristina
authors.initials: K
authors.lastname: Hsieh
authors.forename: Anna A
authors.initials: AA
authors.lastname: Kuang
authors.forename: Mary
authors.initials: M
authors.lastname: Ho
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Morici
authors.forename: Laurel L
authors.initials: LL
authors.lastname: Lenz
authors.forename: Dragana
authors.initials: D
authors.lastname: Cado
authors.forename: Lee W
authors.initials: LW
authors.lastname: Riley
authors.forename: Astar
authors.initials: A
authors.lastname: Winoto
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D017353:Gene Deletion; D006566:Herpesviridae Infections / Q000276:immunology / Q000821:virology; D007113:Immunity, Innate / Q000276:immunology*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018146:Muromegalovirus / Q000276:immunology; D009163:Mycobacterium bovis / Q000276:immunology; D011956:Receptors, Cell Surface / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000821:virology; D053221:TNF-Related Apoptosis-Inducing Ligand; D013997:Time Factors; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505640:Tnfrsf10b protein, mouse; C505654:Tnfsf10 protein, mouse; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha