title: Activation of human macrophages for the killing of intracellular Trypanosoma cruzi by TNF-alpha and IFN-gamma through a nitric oxide-dependent mechanism.
abstract: 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.
authors.affiliation: Centro de Biología Molecular, C-UAM, Universidad Autónoma de Madrid, Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: Muñoz-Fernández
authors.forename: M A
authors.initials: MA
authors.lastname: Fernández
authors.forename: M
authors.initials: M
authors.lastname: Fresno
mesh_terms: 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
chemical_list: D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D001120:Arginine