Adenovirus-induced maturation of dendritic cells through a PI3 kinase-mediated TNF-alpha induction pathway.
Systemic administration of adenovirus and adenovirus vectors induces a robust innate and adaptive immune response in a variety of animal models. In tumor necrosis factor (TNF)(-/-) mice, a diminished immune response to adenovirus (Ad) infection has been attributed to compromised dendritic cell (DC) maturation. In this report, we investigated the mechanisms responsible for Ad-mediated activation and maturation of DC. Ad infection induced high levels of TNF-alpha expression by murine bone marrow-derived DC, comparable to levels observed with lipopolysaccharide exposure. Ad-induced TNF-alpha production was necessary for DC maturation and acts in an autocrine manner. Unlike TNF-alpha production associated with exposure to lipopolysaccharide, Ad induction of TNF-alpha was not dependent on the MyD88 signaling pathway. In contrast, Ad-induced TNF-alpha production and DC maturation were dependent on signaling by phosphoinositide-3-OH kinase (PI3K), as determined by wortmannin and LY294002 blocking experiments. The adenovirus capsid protein penton contains a well characterized arginine-glycine-aspartic acid integrin-binding domain that stimulates PI3K in fibroblast cell lines. When this region of the penton was mutated, TNF-alpha expression and bone marrow-derived DC maturation were attenuated. We propose that integrin-mediated PI3K induction of NF-kappaB activates an autocrine TNF-alpha pathway required for DC maturation in response to Ad.
Philpott
Nicola J
NJ
Molecular Biology Graduate Program, Department of Microbiology and Immunology, Hearst Research Foundation, New York, NY 10021, USA.
Nociari
Marcelo
M
Elkon
Keith B
KB
Falck-Pedersen
Erik
E
D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae / Q000502:physiology*; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects; D017931:DNA Primers; D003713:Dendritic Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88; D009842:Oligopeptides / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016133:Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D017931:DNA Primers; D004791:Enzyme Inhibitors; D053594:Myeloid Differentiation Factor 88; D009842:Oligopeptides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; C507780:Myd88 protein, mouse; C047981:arginyl-glycyl-aspartic acid