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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-
–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.
Received July 14, 2005. Accepted for publication December 8, 2006.
Acknowledgments: The authors thank Dennis Byrne for his technical help and Yannick Vanloubbeeck and Amanda Ramer for their comments on the manuscript.
Financial support: This work was supported by National Institutes of Health grant AI48357. Additional funds were provided by the Office of Biotechnology and the College of Veterinary Medicine at Iowa State University.
* Address correspondence to Douglas E. Jones, College of Veterinary Medicine 2750, Ames, Iowa 50011-1250. E-mail: jonesdou{at}iastate.edu
Authors’ addresses: Rami M. Mukbel, Department of Biological Sciences, 210 Galvin Life Sciences, University of Notre Dame, Notre Dame, IN 46556. Calvin Patten Jr., University of Missouri, Room E-108, Veterinary Medicine Building, 1600 E. Rollins, Columbia, MO 65211. Katherine Gibson, Mousumi Ghosh, Christine Petersen, and Douglas E. Jones, Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, IA 50011-1250, Telephone: +1 (515) 294-3282; Fax: +1 (515) 294-5423, E-mail: jonesdou{at}iastate.edu.
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