Human TNF‐α in transgenic mice induces differential changes in redox status and glutathione‐regulating enzymes

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Abstract
Tumor necrosis factor α (TNF‐α) is a pleiotropic cytokine involved in several diseases. Various effects of TNF‐α 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‐α 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‐α 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‐α in transgenic mice appears to involve marked organ‐specific alterations in glutathione redox status and glutathioneregulating 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‐α and oxidative stress.
Funding Information
  • Norges Forskningsråd
  • Universitetet i Oslo