Selective induction of interleukin-1 production and tumor killing activity of macrophages through apoptosis by the inhibition of oxidative respiration.
Suppression of mitochondrial respiration and increased glycolysis are characteristic features of activated macrophages. We show here that antimycin A, a respiratory inhibitor, induced interleukin-1 synthesis and tumoricidal activity without inducing tumor necrosis factor or nitric oxide. The induction of tumoricidal activity was resistant to inhibitors of tyrosine-specific protein kinases and intracellular glycoprotein transport. The cognate interaction between macrophages and target cells was not a prerequisite for the tumoricidal activity. In contrast, lipopolysaccharide induced the production of interleukin-1, tumor necrosis factor and nitric oxide, the induction of tumoricidal activity being sensitive to genistein and brefeldin A. Antimycin A, like lipopolysaccharide, induced the release of a cytoplasmic enzyme and apoptosis of macrophages. Antimycin A showed anti-metastatic activity in vivo. These results suggest that the inhibition of oxidative respiration would induce apoptosis and the resultant release of soluble effector molecules of macrophages which inhibit tumor metastasis in vivo.
Department of Bioengineering, Tokyo Institute of Technology, Yokohama, Japan.
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Ashikaga
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Honma
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Munemura
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Kataoka
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Endo
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Yamasaki
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Magae
K
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Nagai
D000818:Animals; D000968:Antimycin A / Q000494:pharmacology*; D017209:Apoptosis; D019069:Cell Respiration / Q000187:drug effects*; D007375:Interleukin-1 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000276:immunology; D010101:Oxygen Consumption / Q000187:drug effects*
D007375:Interleukin-1; D008070:Lipopolysaccharides; D000968:Antimycin A