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Infection and Immunity, October 1999, p. 5409-5416, Vol. 67, No. 10
Department of Microbiology, Molecular
Genetics and Immunology, University of Kansas Medical Center,
Kansas City, Kansas 66160-7420
Received 1 April 1999/Returned for modification 22 June
1999/Accepted 23 July 1999
Endotoxemia is accompanied by significant changes in the
reductive-oxidative (redox) balance of critical target organs. Redox stress has been shown to regulate the expression of proinflammatory genes that are induced by endotoxic lipopolysaccharide (LPS) in vitro;
however, much less is known about the effects of redox imbalance on
LPS-induced gene expression in vivo. To assess the effects of redox
stress on inflammatory responses in endotoxemia, mice were treated with
either diethyl maleate (DEM), a glutathione-depleting agent, or
buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis,
and challenged with LPS. While serum tumor necrosis alpha (TNF-
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Redox Imbalance Differentially Inhibits
Lipopolysaccharide-Induced Macrophage Activation in the Mouse
Liver
)
responses and the appearance of TNF--positive Kupffer cells in the
liver were virtually eliminated by DEM or BSO treatment, the expression
of both CD14 and inducible NO synthase (iNOS) by Kupffer cells was
unaffected by glutathione depletion. By contrast, LPS-induced
hepatocyte and hepatic sinusoidal endothelial cell iNOS expression was
significantly inhibited in DEM-treated mice. Hepatocyte iNOS induced by
recombinant mouse TNF- was also inhibited by DEM treatment. These
results indicate that the effects of oxidative stress in this organ are
cell type specific and suggest that both the production and the action
of TNF- are substantially influenced by the redox state of the liver
during endotoxemia.
*
Corresponding author. Mailing address: Department of
Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7420. Phone:
(913) 588-7053. Fax: (913) 588-7295. E-mail:
mparmely{at}kumc.edu.
Infection and Immunity, October 1999, p. 5409-5416, Vol. 67, No. 10
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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