Failure of tumor necrosis factor and interleukin-1 to elicit superoxide production in the mitochondrial matrices of mammalian cells.
Subversion of mitochondrial electron transport to the production of O2.- has been proposed as a mechanism of tumor necrosis factor (TNF)-mediated cell killing and to a lesser extent interleukin-1 (IL-1) and lipopolysaccharide (LPS) cytotoxicity. We utilized the O2.- -sensitive aconitases to measure changes in steady-state 02.- levels in the mitochondrial matrix and cytoplasm of cultured mammalian cells in response to these inflammatory mediators. TNF alpha did not measurably affect aconitase activity, and thus mitochondrial 02.- production, in either cultured human A549 cells or murine L929 cells while TNF alpha clearly caused cytotoxicity as revealed by impaired mitochondrial respiration. IL-1 alpha and Escherichia coli LPS also failed to affect the aconitase activity in A549 cells. Neither the O2.- scavenger Mn(III) TMPyP nor the H2O2 scavenger catalase protected L929 cells against the cytotoxicity of TNF alpha. In conclusion, TNF, IL-1, and LPS do not appear to exert cytotoxicity, or MnSOD gene induction effects, by eliciting mitochondrial O2.- production.
Gardner
P R
PR
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206, USA.
White
C W
CW
D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004579:Electron Transport / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007375:Interleukin-1; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D013482:Superoxide Dismutase; D000154:Aconitate Hydratase