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Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6200-5. Epub 2004 Apr 7.

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

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  • 1Molecular Biology Graduate Program, Department of Microbiology and Immunology, Hearst Research Foundation, New York, NY 10021, USA.

Abstract

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.

PMID:
15071185
[PubMed - indexed for MEDLINE]
PMCID:
PMC395946
Free PMC Article
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