Activation of human macrophages for the killing of intracellular Trypanosoma cruzi by TNF-alpha and IFN-gamma through a nitric oxide-dependent mechanism.
The protozoan parasite Trypanosoma cruzi is able to replicate in the cytoplasm of primary resident macrophages, but is killed by activated macrophages. Pretreatment of human macrophages with recombinant IFN-gamma and to a lesser extent with TNF-alpha, induced a significant trypanocidal activity. Furthermore, TNF-alpha had a synergistic effect with IFN-gamma on macrophage activation in T. cruzi killing. Similarly, IFN-gamma triggered the production of nitric oxide (NO) by macrophages, whereas TNF-alpha was less effective, although it was also synergistic with IFN-gamma. Both NO production and trypanocidal activity, but not superoxide (O2-) generation, induced in macrophages by TNF-alpha or IFN-gamma alone or in combination, were inhibited by N-monomethyl-L-arginine (N-MMLA), a competitive inhibitor of NO synthase activity. Furthermore, a strong correlation was found between the levels of NO production and trypanocidal activity induced by different lymphokine preparations. These results suggest that IFN-gamma and TNF-alpha are involved in the activation of the trypanocidal activity of human macrophages through a NO-dependent mechanism.
Muñoz-Fernández
M A
MA
Centro de Biología Molecular, C-UAM, Universidad Autónoma de Madrid, Spain.
Fernández
M A
MA
Fresno
M
M
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D004357:Drug Synergism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000469:parasitology*; D009569:Nitric Oxide / Q000378:metabolism*; D011994:Recombinant Proteins; D013481:Superoxides / Q000378:metabolism; D014349:Trypanosoma cruzi; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019323:omega-N-Methylarginine
D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D001120:Arginine