The inhibition of arginase by N(omega)-hydroxy-l-arginine controls the growth of Leishmania inside macrophages.
Polyamine synthesis from l-ornithine is essential for Leishmania growth. We have investigated the dependence of Leishmania infection on arginase, which generates l-ornithine, in macrophages from BALB/c, C57BL/6, and nitric oxide synthase II (NOS II)-deficient mouse strains. We have found that N(omega)-hydroxy-l-arginine (LOHA), a physiological inhibitor of arginase, controls cellular infection and also specifically inhibits arginase activity from Leishmania major and Leishmania infantum parasites. The effect was proportional to the course of infection, concentration dependent up to 100 microM, and achieved without an increase in nitrite levels of culture supernatants. Moreover, when the l-arginine metabolism of macrophages is diverted towards ornithine generation by interleukin 4-induced arginase I, parasite growth is promoted. This effect can be reversed by LOHA. Inhibition of NOS II by N(G)-methyl-l-arginine (LNMMA) restores the killing obtained in the presence of interferon (IFN)-gamma plus lipolysaccharide (LPS), whereas the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5,-tetramethylimidazoline-3-oxide-1-oxyl (carboxy-PTIO) was without effect. However, exogenous l-ornithine almost completely inhibits parasite killing when added in the presence of LOHA to macrophages from NOS II-deficient mice or to BALB/c-infected cells activated with IFN-gamma plus LPS. These results suggest that LOHA is an effector molecule involved in the control of Leishmania infection. In addition, macrophage arginase I induction by T helper cell type 2 cytokines could be a mechanism used by parasites to spread inside the host.
Parasitology Unit, Department of Medicine and Animal Health, University of Extremadura, 10071 Cáceres, Spain.
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D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D018314:Leishmania infantum / Q000187:drug effects* / Q000254:growth & development; D018320:Leishmania major / Q000187:drug effects* / Q000254:growth & development; D008264:Macrophages / Q000201:enzymology* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009952:Ornithine / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism
D001565:Benzoates; D004791:Enzyme Inhibitors; D007093:Imidazoles; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; C068309:N(omega)-hydroxyarginine; D001120:Arginine; D009952:Ornithine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D013482:Superoxide Dismutase; D001119:Arginase