Mechanisms of interleukin-2-induced hydrothoraxy in mice: protective effect of endotoxin tolerance and dexamethasone and possible role of reactive oxygen intermediates.
Interleukin (IL)-2 is known to induce vascular leak syndrome (VLS), which was suggested to be mediated by immune system-derived cytokines, including tumor necrosis factor (TNF). To characterize the role of TNF in IL-2 toxicity in C3H/HeN mice, we used two approaches to downregulate TNF production in vivo: treatment with dexamethasone (DEX) and induction of endotoxin (lipopolysaccharide) (LPS) tolerance by a 4-day pretreatment with LPS (35 micrograms/mouse/day). Mice were then treated with IL-2 for 5 days (1.8 x 10(5) IU/mouse, twice daily). Both DEX and LPS tolerance blocked development of hydrothorax in IL-2-treated mice and inhibited TNF induction. DEX and LPS tolerance also ameliorated IL-2 toxicity in terms of decrease in food intake and inhibited the increase of the acute-phase protein, serum amyloid A (SAA). The IL-2 activation of splenic natural killer (NK) cell activity was also diminished by DEX and, to a lesser extent, by LPS-tolerance. Treatment with IL-2 also caused induction of the superoxide-generating enzyme xanthine oxidase (XO) in tissues and serum and induced bacterial translocation in the mesenteric lymph nodes (MLN). These data suggest that multiple mechanisms, including NK cell activity, cytokines, and reactive oxygen intermediates, might be important in the vascular toxicity of IL-2.
Mario Negri Institute for Pharmacological Research, Milano, Italy.
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Faggioni
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Allavena
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Cantoni
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Carelli
M T
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Demitri
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Delgado
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Gatti
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Gnocchi
A M
AM
Isetta
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Paganin
D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology*; D006876:Hydrothorax / Q000139:chemically induced*; D007376:Interleukin-2 / Q000633:toxicity*; D007694:Killer Cells, Natural / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D017382:Reactive Oxygen Species / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014969:Xanthine Oxidase / Q000378:metabolism
D007376:Interleukin-2; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D014969:Xanthine Oxidase