B activation and cytokine production
Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Correspondence: Michael D. Wheeler, CB# 7365 Mary Elllen Jones Building, Chapel Hill, NC 27599. E-mail: wheelmi{at}med.unc.edu
Kupffer cells play a significant role in the pathogenesis of several
liver diseases; therefore, a potential therapeutic strategy would be to
inactivate the Kupffer cell with a gene-delivery system. Although
recombinant adenovirus provides robust, transgene expression in
parenchymal cells, whether adenovirus transduces Kupffer cells is
unclear. Thus, the purpose of this study was to evaluate this
possibility. In animals infected with adenovirus, Kupffer cells were
identified positively to express adenoviral transgenes by
immunohistochemical techniques and Western blot analysis, indicating
that Kupffer cells are transduced in vivo. Indeed, isolated
Kupffer cells were transduced in vitro with recombinant
adenovirus in a dose-dependent manner. Moreover, adenoviral
transduction of Kupffer cells was blocked by inhibitors of 
Vß5
integrin, the co-receptor for adenovirus binding, supporting the
hypothesis that adenovirus transduces Kupffer cells via an Vß5
integrin-dependent mechanism. Indeed, it is shown here that Kupffer
cells express Vß5 integrins. In a functional assay, infection of
isolated Kupffer cells with adenovirus containing superoxide dismutase
or I
B super-repressor blunted LPS-induced nuclear transcription
factor kappa B (NF-B) activation and tumor necrosis factor
(TNF-) production but not IL-10 production. Moreover, superoxide
production was blocked by expression of superoxide dismutase. These
data support the hypothesis that LPS-induced NF-B activation and
TNF- production in Kupffer cells are oxidant-dependent. These
findings suggest that Kupffer cell-targeted approaches may be a
potential therapeutic strategy against many inflammatory diseases
including early alcohol-induced liver injury.
Key Words: alpha V beta 5 integrins • TNF- • superoxide dismutase • IB
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