title: Macrophage killing of Leishmania amazonensis amastigotes requires both nitric oxide and superoxide.
abstract: The requirements for effective and efficient intracellular killing of Leishmania amazonensis by activated macrophages are unknown. Despite resistance to the arginase inhibitor LOHA by intracellular L. amazonensis amastigotes, enhanced replication did not account for the relative resistance of this parasite to macrophage activation. Herein we report that the presence of both superoxide and nitric oxide is necessary for efficient killing of L. amazonensis amastigotes within LPS/IFN-gamma-activated bone marrow-derived macrophages generated from C3H mice. Addition of an extracellular signal-regulated kinase (ERK) inhibitor to L. amazonensis-infected macrophages increased the ability of these activated macrophages to kill L. amazonensis amastigotes. This enhanced macrophage killing through addition of ERK inhibitor was abrogated by inhibition of superoxide or iNOS, whereas inhibiting superoxide had no effect on the killing of L. major. These results suggest that ERK activation may modulate effective macrophage killing, leading to the ability of L. amazonensis to resist elimination within activated macrophages.
authors.affiliation: Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Rami M
authors.initials: RM
authors.lastname: Mukbel
authors.forename: Calvin
authors.initials: C
authors.lastname: Patten
authors.forename: Katherine
authors.initials: K
authors.lastname: Gibson
authors.forename: Mousumi
authors.initials: M
authors.lastname: Ghosh
authors.forename: Christine
authors.initials: C
authors.lastname: Petersen
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Jones
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D007891:Leishmania / Q000254:growth & development* / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*
chemical_list: D005419:Flavonoids; D013481:Superoxides; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one