title: L-Arginine availability modulates local nitric oxide production and parasite killing in experimental trypanosomiasis.
abstract: Nitric oxide (NO) is an important effector molecule of the immune system in eliminating numerous pathogens. Peritoneal macrophages from Trypanosoma brucei brucei-infected mice express type II NO synthase (NOS-II), produce NO, and kill parasites in the presence of L-arginine in vitro. Nevertheless, parasites proliferate in the vicinity of these macrophages in vivo. The present study shows that L-arginine availability modulates NO production. Trypanosomes use L-arginine for polyamine synthesis, required for DNA and trypanothione synthesis. Moreover, arginase activity is up-regulated in macrophages from infected mice from the first days of infection. Arginase competes with NOS-II for their common substrate, L-arginine. In vitro, arginase inhibitors decreased urea production, increased macrophage nitrite production, and restored trypanosome killing. In vivo, a dramatic decrease in L-arginine concentration was observed in plasma from infected mice. In situ restoration of NO production and trypanosome killing were observed when excess L-arginine, but not D-arginine or L-arginine plus N(omega)-nitro-L-arginine (a NOS inhibitor), was injected into the peritoneum of infected mice. These data indicate the role of L-arginine depletion, induced by arginase and parasites, in modulating the L-arginine-NO pathway under pathophysiological conditions.
authors.affiliation: Laboratoire de Parasitologie, Université Bordeaux II, Bordeaux, France.
authors.forename: A P
authors.initials: AP
authors.lastname: Gobert
authors.forename: S
authors.initials: S
authors.lastname: Daulouede
authors.forename: M
authors.initials: M
authors.lastname: Lepoivre
authors.forename: J L
authors.initials: JL
authors.lastname: Boucher
authors.forename: B
authors.initials: B
authors.lastname: Bouteille
authors.forename: A
authors.initials: A
authors.lastname: Buguet
authors.forename: R
authors.initials: R
authors.lastname: Cespuglio
authors.forename: B
authors.initials: B
authors.lastname: Veyret
authors.forename: P
authors.initials: P
authors.lastname: Vincendeau
mesh_terms: D000818:Animals; D001119:Arginase / Q000032:analysis / Q000037:antagonists & inhibitors; D001120:Arginine / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000032:analysis; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000276:immunology*; D014353:Trypanosomiasis, African / Q000276:immunology*
chemical_list: D009573:Nitrites; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D001119:Arginase