Human TNF-alpha in transgenic mice induces differential changes in redox status and glutathione-regulating enzymes.
Tumor necrosis factor a (TNF-alpha) is a pleiotropic cytokine involved in several diseases. Various effects of TNF-alpha are mediated by the induction of a cellular state consistent with oxidative stress. Glutathione (GSH) is a major redox-buffer of eukaryotic cells and is important in the defense against oxidative stress. We hypothesized that persistent TNF-alpha secretion could induce oxidative stress through modulation of GSH metabolism. This hypothesis was examined in a transgenic mouse model with low, persistent expression of human TNF-alpha in the T cell compartment. Major findings were i) marked tissue-specific changes in GSH redox status and GSH regulating enzymes, with the most pronounced changes in liver; ii) moderate changes in GSH metabolism and up-regulation of GSH-regulating enzymes were observed in lung and kidney from transgenic mice; and iii) liver, lung and kidney from transgenic mice had decreased levels of total glutathione, whereas splenic CD4+ and CD8+ T cells had a marked increase in oxidized glutathione as the major change. Oxidative stress induced by persistent low-grade exposure to TNF-alpha in transgenic mice appears to involve marked organ-specific alterations in glutathione redox status and glutathione-regulating enzymes with the most pronounced changes in the liver. These mice constitute a useful model for immunodeficiency syndromes and chronic inflammatory diseases involving pathogenic interaction between TNF-alpha and oxidative stress.
Biotechnology Centre of Oslo, University of Oslo, PB 1125 Blindern, 0317 Oslo, Norway.
Heidi
H
Glosli
Karl Johan
KJ
Tronstad
Hege
H
Wergedal
Fredrik
F
Müller
Asbjørn
A
Svardal
Pål
P
Aukrust
Rolf Kristian
RK
Berge
Hans
H
Prydz
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D013601:T-Lymphocytes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
D000975:Antioxidants; D014409:Tumor Necrosis Factor-alpha; D005978:Glutathione