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.