Macrophage deactivating factor and transforming growth factors-beta 1 -beta 2 and -beta 3 inhibit induction of macrophage nitrogen oxide synthesis by IFN-gamma.
Macrophage deactivating factor (MDF) and three members of the transforming growth factor-beta family (TGF-beta 1, -beta 2, and -beta 3) blocked the ability of IFN-gamma to induce release of reactive nitrogen intermediates from mouse peritoneal macrophages. Raising the concentration of IFN-gamma did not diminish the potency of the inhibitors (50% inhibition by approximately 7 nM MDF, 2 pM TGF-beta 1, 4 pM TGF-beta 2, and 8 pM TGF-beta 3). These inhibitors partially blocked induction of nitrite release in macrophages activated with the combination of IFN-gamma plus TNF-alpha, but were incapable of inhibiting when macrophages were activated by the combination of IFN-gamma plus LPS. MDF and TGF-beta 1, -beta 2, and -beta 3 inhibited IFN-gamma-induced nitrite release only if present during the induction phase; once IFN-gamma-nitrite release had commenced, addition of the same cytokines was no longer inhibitory. Maximum inhibition of synthesis over a 48-h period required that the inhibitors be present during the first 3 h of induction. Thus, cytokines can suppress as well as induce macrophage synthesis of reactive nitrogen intermediates, products with cytotoxic, antimicrobial, and vasodilatory properties.
Ding
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Beatrice and Samuel A. Seaver Laboratory, Cornell University Medical College, New York, NY 10021.
Nathan
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CF
Graycar
J
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Derynck
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Stuehr
D J
DJ
Srimal
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D000818:Animals; D001685:Biological Factors / Q000494:pharmacology*; D016207:Cytokines; D005260:Female; D007371:Interferon-gamma / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009589:Nitrogen Oxides / Q000378:metabolism*; D015291:Transforming Growth Factors / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D001685:Biological Factors; D016207:Cytokines; D008070:Lipopolysaccharides; D009589:Nitrogen Oxides; D014409:Tumor Necrosis Factor-alpha; D015291:Transforming Growth Factors; D007371:Interferon-gamma