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

doi:10.1073/pnas.0308368101

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

^*Molecular Biology Graduate Program, Department of Microbiology and Immunology, Hearst Research Foundation, and ^†Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021; and ^‡Department of Medicine and Immunology, University of Washington School of Medicine, Seattle, WA 98195

Edited by Kenneth I. Berns, University of Florida, Gainesville, FL (received for review December 16, 2003)

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-α expression by murine bone marrow-derived DC, comparable to levels observed with lipopolysaccharide exposure. Ad-induced TNF-α production was necessary for DC maturation and acts in an autocrine manner. Unlike TNF-α production associated with exposure to lipopolysaccharide, Ad induction of TNF-α was not dependent on the MyD88 signaling pathway. In contrast, Ad-induced TNF-α 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-α expression and bone marrow-derived DC maturation were attenuated. We propose that integrin-mediated PI3K induction of NF-κB activates an autocrine TNF-α pathway required for DC maturation in response to Ad.

Footnotes

↵ § To whom correspondence should be addressed at: Weill Medical College of Cornell University, Department of Microbiology and Immunology, Box 62, 1300 York Avenue, New York, NY 10021. E-mail: efalckp{at}med.cornell.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: TNF, tumor necrosis factor; Ad, adenovirus; DC, dendritic cell; BMDC, bone marrow-derived DC; LPS, lipopolysaccharide; TLR, Toll-like receptor; βgal, β-galactosidase; RGD, arginine-glycine-aspartic acid; CAR, coxsackie adenovirus receptor; PE, phycoerythrin; KO, knockout; MFI, mean fluorescence intensity; PI3K, phosphoinositide-3-OH kinase.