Adenovirus-induced maturation of dendritic cells through a PI3 kinase-mediated TNF-alpha induction pathway.

TitleAdenovirus-induced maturation of dendritic cells through a PI3 kinase-mediated TNF-alpha induction pathway.
Publication TypeJournal Article
Year of Publication2004
AuthorsPhilpott NJ, Nociari M, Elkon KB, Falck-Pedersen E
JournalProc Natl Acad Sci U S A
Date Published2004 Apr 20
KeywordsAdaptor Proteins, Signal Transducing, Adenoviridae, Animals, Antigens, Differentiation, Base Sequence, Cell Differentiation, Dendritic Cells, DNA Primers, Enzyme Inhibitors, Mice, Mice, Inbred C57BL, Myeloid Differentiation Factor 88, Oligopeptides, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Polymerase Chain Reaction, Receptors, Immunologic, Tumor Necrosis Factor-alpha

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.

Alternate JournalProc Natl Acad Sci U S A
PubMed ID15071185
PubMed Central IDPMC395946
Grant ListK01 HL070438 / HL / NHLBI NIH HHS / United States
P01 HL051746 / HL / NHLBI NIH HHS / United States
K01 HL70438-01 / HL / NHLBI NIH HHS / United States
P50 HL51746 / HL / NHLBI NIH HHS / United States

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