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Inhibition of tumor cell mitochondrial respiration by macrophage cytotoxic mediators distinct from interferon
Author(s) -
Tucker Stanley D.,
Auzenne Edmond J.,
Sivaramakrishnan Mathoor R.
Publication year - 1993
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.53.2.138
Subject(s) - cytotoxic t cell , biology , lipopolysaccharide , macrophage , tumor necrosis factor alpha , nitric oxide , interferon , microbiology and biotechnology , immunology , in vitro , biochemistry , endocrinology
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‐γ (IFN‐γ) in combination with tumor necrosis factor, interleukin‐1, or lipopolysaccharide. Conditioned supernatants obtained from activated macrophages appear to contain interferon‐γ, suggesting that inhibition of mitochondrial respiration in tumor cells was caused by synergy of IFN‐γ 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‐γ 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‐γ. Treatment of the EA13.5 cell‐conditioned supernatants with neutralizing antibody against IFN‐γ 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‐γ are involved in the induction of nitric oxide synthesis and inhibition of mitochondrial respiration in tumor cells.