Statins fail to improve outcome in experimental cerebral malaria and potentiate Toll-like receptor-mediated cytokine production by murine macrophages.
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.
Helmers
Andrew J
AJ
Institute of Medical Science, and Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Gowda
D Channe
DC
Kain
Kevin C
KC
Liles
W Conrad
WC
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D016779:Malaria, Cerebral / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018512:Parasitemia; D010962:Plasmodium berghei; D019821:Simvastatin / Q000494:pharmacology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
D000962:Antimalarials; D015850:Interleukin-6; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D019821:Simvastatin