Redox imbalance differentially inhibits lipopolysaccharide-induced macrophage activation in the mouse liver.
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-alpha) responses and the appearance of TNF-alpha-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-alpha 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-alpha are substantially influenced by the redox state of the liver during endotoxemia.
Wang
F
F
Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas 66160-7420, USA.
Wang
L Y
LY
Wright
D
D
Parmely
M J
MJ
D000818:Animals; D005260:Female; D005978:Glutathione / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects*; D008298:Maleates / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010084:Oxidation-Reduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D008070:Lipopolysaccharides; D008298:Maleates; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C014476:diethyl maleate; D005978:Glutathione