Interferon-gamma and tumor necrosis factor induce the L-arginine-dependent cytotoxic effector mechanism in murine macrophages.
We tested several monokines and muramyl dipeptide (MDP) to determine whether they induce the L-arginine-dependent effector mechanism in cultured murine macrophages. Recombinant interferon-gamma (rIFN-gamma) and recombinant tumor necrosis factor (rTNF) synergize to induce nitrite (NO2-) and nitrate (NO3-) synthesis from L-arginine as well as to cause inhibition of the iron-dependent enzyme aconitase in macrophages. Unlike rTNF, recombinant interleukin 1 (rIL 1) and rIL 6/B cell stimulatory factor 2 (rIL 6/BSF-2) did not act as cofactors when added to macrophages in the presence of rIFN-gamma. rIFN-gamma plus MDP induced the L-arginine-dependent effector mechanism in murine macrophages. However, induction by rIFN-gamma plus MDP was inhibited by anti-rTNF antibodies which suppressed both NO2-/NO3- synthesis and aconitase inhibition. This result indicates that endogenously produced TNF is involved in the induction of the L-arginine-dependent effector mechanism when MDP is the co-stimulant with rIFN-gamma. In contrast, anti-rTNF antibodies did not fully suppress the effect of combining rIFN-gamma and lipopolysaccharide, suggesting that, in this case, activation of the L-arginine-dependent effector pathway may involve more than induction of TNF synthesis by the macrophages. These results provide information, at a biochemical level, on a mechanism through which combination of IFN-gamma and TNF can modulate macrophage functions involved in the control of cell proliferation.
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D000937:Antigen-Antibody Reactions; D001120:Arginine / Q000502:physiology*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D004357:Drug Synergism; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology*; D007506:Iron-Sulfur Proteins / Q000037:antagonists & inhibitors; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007506:Iron-Sulfur Proteins; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D007371:Interferon-gamma; D001120:Arginine; D000154:Aconitate Hydratase