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Statins Fail to Improve Outcome in Experimental Cerebral Malaria and Potentiate Toll-Like Receptor-Mediated Cytokine Production by Murine Macrophages

Andrew J. Helmers, D. Channe Gowda, Kevin C. Kain, AND W. Conrad Liles^*,

Cerebral malaria is responsible for a large proportion of the estimated one million deaths caused by Plasmodium falciparum malaria annually. This disease is associated with excessive pro-inflammatory cytokine production resulting from dysregulated host responses to infection. On the basis of reports indicating potent activity against host-mediated inflammatory disorders such as sepsis, we examined the activity of statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) on malaria-associated inflammation in vivo and in vitro. Simvastatin failed to improve survival or alter parasitemia in C57BL/6 mice infected with Plasmodium berghei ANKA, an experimental model of cerebral malaria. In vitro statin treatment potentiated production of tumor necrosis factor and interleukin-6 by murine peritoneal macrophages in response to P. falciparum glycosylphosphatidyl inositol, a Toll-like receptor 2 (TLR2) ligand. Statin treatment also potentiated pro-inflammatory cytokine production stimulated by a panel of TLR2 and TLR4 ligands. Our results indicate that statins fail to confer protection in experimental cerebral malaria and potentiate TLR-mediated pro-inflammatory cytokine production by primary murine macrophages.

Received April 21, 2009. Accepted for publication June 16, 2009.

Acknowledgments: We thank Dr. Constance Finney for invaluable help with the acquisition and analysis of the flow cytometry data in this study, and Dr. Michael Hawkes for advice regarding statistical analysis. This work was presented at the American Society of Tropical Medicine and Hygiene 56th Annual Meeting, Philadelphia, PA, November 4–8, 2007.

Financial support: This work was supported by grants from the Canadian Institutes of Health Research (Team Grant in Malaria CTP 79842 [Kevin C. Kain, Principal Investigator] and MT-13721 [Kevin C. Kain]), by Genome Canada through the Ontario Genomics Institute, and by research funding from the McLaughlin Centre for Molecular Medicine (Kevin C. Kain and W. Conrad Liles). Andrew J. Helmers is supported by a Canada Institutes of Health Research (CIHR) Research Studentship, Kevin C. Kain by a CIHR Canada Research Chair in Molecular Parasitology, and W. Conrad Liles by a CIHR Canada Research Chair in Infectious Diseases and Inflammation.

^* Address correspondence to W. Conrad Liles, Toronto General Hospital 13E 214, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada. E-mail: conrad.liles{at}uhn.on.ca

These authors contributed equally to this work.

Note: Supplementary Figure 1 (Atorvastatin increases TLR2/4-induced TNF production by primary murine macrophages in vitro) and Supplementary Figure 2 (Atorvastatin increases TLR2/4-induced IL-6 production by primary murine macrophages in vitro) appear online at www.ajtmh.org.

Authors’ addresses: Andrew J. Helmers, Kevin C. Kain, and W. Conrad Liles, Toronto General Hospital 13E 214, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada, E-mail: conrad.liles{at}uhn.on.ca. D. Channe Gowda, Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA 17033, E-mail: gowda{at}psu.edu.