IFN-gamma-induced TNF-alpha is a prerequisite for in vitro production of nitric oxide generated in murine peritoneal macrophages by IFN-gamma.
The effect of IFN-gamma to stimulate formation of nitric oxide (NO) by normal murine peritoneal macrophages (M phi) has been found to be completely dependent on the ability of IFN-gamma to activate secretion of TNF-alpha. The NO-stimulatory effect of IFN-gamma was abolished by anti-TNF-alpha antibodies, the inhibitory intervention of which could be fully reversed by exogenously supplied TNF-alpha. Accordingly, the failure of M phi from C3H/HeJ mice to secrete TNF-alpha upon stimulation with IFN-gamma was associated with their complete incapability to generate NO, unless they were simultaneously treated with IFN-gamma + TNF-alpha. Collectively, the data document that similar to the NO up-regulatory action of other cytokines, the effect of IFN-gamma is not independent, but depends on a synergistic cooperation with the self-produced TNF-alpha. The findings thus indicate that a widespread opinion claiming that IFN-gamma per se is able to stimulate biosynthesis of NO needs revision.
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Laboratory of Immunology, Academy of Sciences of the Czech Republic, Prague, Czech Republic. daniela@biomed.cas.cz
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D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D007371:Interferon-gamma / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis*; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma