Differentiation of murine macrophages to express nonspecific cytotoxicity for tumor cells results in L-arginine-dependent inhibition of mitochondrial iron-sulfur enzymes in the macrophage effector cells.
Previous studies show that cytotoxic activated macrophages cause a reproducible pattern of metabolic inhibition in viable tumor target cells. This includes inhibition of DNA synthesis, two oxidoreductases of the mitochondrial electron transport chain (NADH: ubiquinone oxidoreductase and succinate: ubiquinone oxidoreductase), and the citric acid cycle enzyme aconitase. This pattern of metabolic inhibition is induced by a cytotoxic activated macrophage associated biochemical pathway with L-arginine deimination activity that synthesizes L-citrulline from L-arginine and oxygenated nitrogen derivatives from the imino nitrogen removed from the guanido group of L-arginine. Here we report that macrophages activated in vivo by infection with bacillus Calmette-Guérin or in vitro by murine rIFN-gamma or murine IFN-alpha/beta (in the presence of the second signal LPS in all cases) develop inhibition of aconitase and the same two oxidoreductases of the mitochondrial electron transport chain as was documented earlier in target cells of cytotoxic activated macrophages. In addition, this pattern of metabolic inhibition which develops in cytotoxic activated macrophages is caused by the L-arginine-dependent effector mechanism. Inhibition of mitochondrial respiration by effectors of the L-arginine-dependent cytotoxicity system results in a compensatory increase in activity of the glycolytic pathway. We speculate that the pattern of metabolic inhibition induced in cytotoxic activated macrophages by the L-arginine-dependent effector system causes changes in the macrophage intracellular environment that increases resistance to certain facultative and obligate intracellular pathogens.
D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors; D000818:Animals; D001120:Arginine / Q000502:physiology*; D002454:Cell Differentiation; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D004579:Electron Transport; D007372:Interferons / Q000494:pharmacology; D007506:Iron-Sulfur Proteins / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008667:Metalloproteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008809:Mice, Inbred C3H; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D009163:Mycobacterium bovis / Q000276:immunology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology
D007506:Iron-Sulfur Proteins; D008070:Lipopolysaccharides; D008667:Metalloproteins; D011994:Recombinant Proteins; D007372:Interferons; D001120:Arginine; D010088:Oxidoreductases; D000154:Aconitate Hydratase