Inhibition of tumor cell mitochondrial respiration by macrophage cytotoxic mediators distinct from interferon-gamma.

Abstract

Macrophage-mediated inhibition of mitochondrial respiration in EMT-6 murine mammary adenocarcinoma cells can be mimicked in vitro by treatment of the cells with interferon-gamma (IFN-gamma) in combination with tumor necrosis factor, interleukin-1, or lipopolysaccharide. Conditioned supernatants obtained from activated macrophages appear to contain interferon-gamma, suggesting that inhibition of mitochondrial respiration in tumor cells was caused by synergy of IFN-gamma with other cytokines. To further characterize monokines that cause inhibition of mitochondrial respiration in tumor cells, EA13.5 macrophage-like cells were isolated and selected for inhibition of mitochondrial respiration in EMT-6 tumor cells. After stimulation with IFN-gamma and lipopolysaccharide, the EA13.5 cells released into conditioned supernatants a cytotoxic mediator that induced nitric oxide synthesis and caused lesions in the electron transport chain of EMT-6 cells similar to the lesions caused by activated peritoneal macrophages. Enzyme-linked immunosorbent assay demonstrated that the conditioned supernatants produced by EA13.5 macrophage cells did not contain IFN-gamma. Treatment of the EA13.5 cell-conditioned supernatants with neutralizing antibody against IFN-gamma did not abrogate the inhibition of mitochondrial respiration in EMT-6 cells caused by these conditioned supernatants. This study demonstrated that unidentified macrophage cytotoxic mediators distinct from IFN-gamma are involved in the induction of nitric oxide synthesis and inhibition of mitochondrial respiration in tumor cells.

• Authors: S D Tucker, E J Auzenne, M R Sivaramakrishnan
• Journal: Journal of leukocyte biology (J Leukoc Biol) Vol. 53 Issue 2 Pg. 138-43 (Feb 1993) ISSN: 0741-5400 [Print] United States
• PMID: 8445326 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Culture Media, Conditioned
• Cytokines
• Interleukin-1
• Lipopolysaccharides
• Tumor Necrosis Factor-alpha
• Rotenone
• Antimycin A
• Interferon-gamma

Topics

• Adenocarcinoma
• Animals
• Antimycin A (pharmacology)
• Cell Line
• Culture Media, Conditioned
• Cytokines (pharmacology, physiology)
• Interferon-gamma (pharmacology)
• Interleukin-1 (pharmacology)
• Kinetics
• Lipopolysaccharides (pharmacology)
• Macrophages (drug effects, physiology)
• Mammary Neoplasms, Experimental
• Mice
• Mitochondria (drug effects, metabolism)
• Oxygen Consumption (drug effects)
• Rotenone (pharmacology)
• Tumor Cells, Cultured
• Tumor Necrosis Factor-alpha (pharmacology)