Experimental leishmaniasis: synergistic effect of ion channel blockers and interferon-gamma on the clearance of Leishmania major by macrophages.
We have previously shown that cultured Leishmania promastigotes are sensitive to drugs blocking K+ and Na+ channels and Na+/H+ transport systems and that the percentage of parasite-infected macrophages decreases significantly in the presence of the drugs. In the present work, we analyzed whether this drug susceptibility of intracellular amastigotes was associated with the activation of macrophage microbicidal mechanisms. Pretreatment of the cells with glibenclamide (GLIB) increased their resistance to infection with Leishmania, an effect that may be mediated by calcium fluxes since it was reversed by ethylene glycol bis-(beta-aminoethyl ether)-N,N,N',N-tetraacetic acid (EGTA). It was noteworthy that in infected macrophages post-treated with the drugs the clearance of parasites was strongly enhanced when the cells were treated simultaneously with GLIB and interferon-gamma; this effect correlated with an increased production of reactive nitrogen intermediates. In conclusion, the data suggest that GLIB treatment increases the resistance of macrophages to infection with Leishmania and potentiates the interferon-gamma-stimulated clearance of parasites via the induction of nitric oxide.
Ponte-Sucre
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Laboratory of Molecular Physiology, Instituto de Medicina Experimental, Facultad de Medicina, Universidad Central de Venezuela, Caracas. alponte@reaccium.de
Mendoza-León
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Moll
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D000818:Animals; D002478:Cells, Cultured; D004357:Drug Synergism; D005905:Glyburide / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018320:Leishmania major / Q000187:drug effects* / Q000472:pathogenicity; D016773:Leishmaniasis, Cutaneous / Q000469:parasitology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology* / Q000469:parasitology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000096:biosynthesis; D016897:Respiratory Burst
D007473:Ion Channels; D009569:Nitric Oxide; D007371:Interferon-gamma; D005905:Glyburide