title: Arginase I induction in macrophages, triggered by Th2-type cytokines, supports the growth of intracellular Leishmania parasites.
abstract: Leishmania spp. are intracellular protozoan parasites that invade and replicate within macrophages. In a previous report, we have demonstrated that the growth of intracellular amastigotes could be controlled by inhibition of arginase. This enzyme, induced in host cells by Th2 cytokines, synthesizes L-ornithine which can be used by parasites to generate polyamines and proliferate. In this study, we have designed experiments to better analyse the dependence of parasite proliferation on arginase induction in infected macrophages. Treatment of Leishmania major-infected BALB/c macrophages with interleukin (IL)-4, IL-10 or transforming growth factor-beta, which are all inducers of arginase I in murine macrophages, led to a proportional increase in the number of intracellular amastigotes. Moreover, parasite proliferation and arginase activity levels in macrophages from the susceptible BALB/c mice were significantly higher than those from infected C57BL/6 cells when treated with identical doses of these cytokines, indicating that a strong correlation exist between the permissibility of host cells to L. major infection and the induction of arginase I in macrophages. Specific inhibition of arginase by N(omega)-hydroxy-nor-L-arginine (nor-LOHA) reverted growth, while L-ornithine and putrescine promoted parasite proliferation, indicating that the parasite cell division depends critically on the level of L-ornithine available in the host. Therefore, arginase induction in the context of a Th2 predominant response might be a contributor to susceptibility in leishmaniasis.
authors: Parasitology Unit, Department of Medicine and Animal Health, Faculty of Veterinary Medicine, Cáceres, Spain.
authors: Virginia
authors: V
authors: Iniesta
authors: L Carlos
authors: LC
authors: Gómez-Nieto
authors: Isabel
authors: I
authors: Molano
authors: Alicia
authors: A
authors: Mohedano
authors: Jesualdo
authors: J
authors: Carcelén
authors: Cristina
authors: C
authors: Mirón
authors: Carlos
authors: C
authors: Alonso
authors: Inés
authors: I
authors: Corraliza
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis* / Q000502:physiology; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D016753:Interleukin-10 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D018320:Leishmania major / Q000254:growth & development*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000469:parasitology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009952:Ornithine / Q000378:metabolism; D011700:Putrescine / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D016207:Cytokines; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4; C068309:N(omega)-hydroxyarginine; D001120:Arginine; D009952:Ornithine; D001119:Arginase; D011700:Putrescine