• 1

    Mohan A, Sharma SK, Bollineni S, 2008. Acute lung injury and acute respiratory distress syndrome in malaria. J Vector Borne Dis 45 :179–193.

    • Search Google Scholar
    • Export Citation
  • 2

    Carcillo JA, 2005. Reducing the global burden of sepsis in infants and children: a clinical practice research agenda. Pediatr Crit Care Med 6 :S157–S164.

    • Search Google Scholar
    • Export Citation
  • 3

    Hunt NH, Grau GE, 2003. Cytokines: accelerators and brakes in the pathogenesis of cerebral malaria. Trends Immunol 24 :491–499.

  • 4

    Abraham E, Singer M, 2007. Mechanisms of sepsis-induced organ dysfunction. Crit Care Med 35 :2408–2416.

  • 5

    Ekland EH, Fidock DA, 2007. Advances in understanding the genetic basis of antimalarial drug resistance. Curr Opin Microbiol 10 :363–370.

    • Search Google Scholar
    • Export Citation
  • 6

    Jain MK, Ridker PM, 2005. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov 4 :977–987.

  • 7

    Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, Pfeffer MA, Braunwald E, Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22(PROVE IT-TIMI 22) Investigators, 2005. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 352 :20–28.

    • Search Google Scholar
    • Export Citation
  • 8

    Wenke K, Meiser B, Thiery J, Reichart B, 2005. Impact of simvastatin therapy after heart transplantation an 11-year prospective evaluation. Herz 30 :431–432.

    • Search Google Scholar
    • Export Citation
  • 9

    Maki-Petaja KM, Booth AD, Hall FC, Wallace SM, Brown J, McEniery CM, Wilkinson IB, 2007. Ezetimibe and simvastatin reduce inflammation, disease activity, and aortic stiffness and improve endothelial function in rheumatoid arthritis. J Am Coll Cardiol 50 :852–858.

    • Search Google Scholar
    • Export Citation
  • 10

    Merx MW, Liehn EA, Graf J, van de Sandt A, Schaltenbrand M, Schrader J, Hanrath P, Weber C, 2005. Statin treatment after onset of sepsis in a murine model improves survival. Circulation 112 :117–124.

    • Search Google Scholar
    • Export Citation
  • 11

    Merx MW, Liehn EA, Janssens U, Lutticken R, Schrader J, Hanrath P, Weber C, 2004. HMG-CoA reductase inhibitor simvastatin profoundly improves survival in a murine model of sepsis. Circulation 109 :2560–2565.

    • Search Google Scholar
    • Export Citation
  • 12

    Ando H, Takamura T, Ota T, Nagai Y, Kobayashi K, 2000. Cerivastatin improves survival of mice with lipopolysaccharide-induced sepsis. J Pharmacol Exp Ther 294 :1043–1046.

    • Search Google Scholar
    • Export Citation
  • 13

    Chen CH, Lee RP, Wu WT, Liao KW, Hsu N, Hsu BG, 2007. Fluvastatin ameliorates endotoxin induced multiple organ failure in conscious rats. Resuscitation 74 :166–174.

    • Search Google Scholar
    • Export Citation
  • 14

    Chaudhry MZ, Wang JH, Blankson S, Redmond HP, 2008. Statin (cerivastatin) protects mice against sepsis-related death via reduced proinflammatory cytokines and enhanced bacterial clearance. Surg Infect (Larchmt) 9 :183–194.

    • Search Google Scholar
    • Export Citation
  • 15

    Greenwood J, Walters CE, Pryce G, Kanuga N, Beraud E, Baker D, Adamson P, 2003. Lovastatin inhibits brain endothelial cell rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. FASEB J 17 :905–907.

    • Search Google Scholar
    • Export Citation
  • 16

    McKay A, Leung BP, McInnes IB, Thomson NC, Liew FY, 2004. A novel anti-inflammatory role of simvastatin in a murine model of allergic asthma. J Immunol 172 :2903–2908.

    • Search Google Scholar
    • Export Citation
  • 17

    Kim DY, Ryu SY, Lim JE, Lee YS, Ro JY, 2007. Anti-inflammatory mechanism of simvastatin in mouse allergic asthma model. Eur J Pharmacol 557 :76–86.

    • Search Google Scholar
    • Export Citation
  • 18

    Gowda DC, 2007. TLR-mediated cell signaling by malaria GPIs. Trends Parasitol 23 :596–604.

  • 19

    de Souza JB, Riley EM, 2002. Cerebral malaria: the contribution of studies in animal models to our understanding of immunopathogenesis. Microbes Infect 4 :291–300.

    • Search Google Scholar
    • Export Citation
  • 20

    Matsumoto M, Einhaus D, Gold ES, Aderem A, 2004. Simvastatin augments lipopolysaccharide-induced proinflammatory responses in macrophages by differential regulation of the c-fos and c-jun transcription factors. J Immunol 172 :7377–7384.

    • Search Google Scholar
    • Export Citation
  • 21

    Serghides L, Kain KC, 2001. Peroxisome proliferator-activated receptor gamma-retinoid X receptor agonists increase CD36-dependent phagocytosis of Plasmodium falciparum-parasitized erythrocytes and decrease malaria-induced TNF-alpha secretion by monocytes/macrophages. J Immunol 166 :6742–6748.

    • Search Google Scholar
    • Export Citation
  • 22

    Sakai H, Hisamoto S, Fukutomi I, Sou K, Takeoka S, Tsuchida E, 2004. Detection of lipopolysaccharide in hemoglobin-vesicles by limulus amebocyte lysate test with kinetic-turbidimetric gel clotting analysis and pretreatment of surfactant. J Pharm Sci 93 :310–321.

    • Search Google Scholar
    • Export Citation
  • 23

    Krishnegowda G, Hajjar AM, Zhu J, Douglass EJ, Uematsu S, Akira S, Woods AS, Gowda DC, 2005. Induction of proinflammatory responses in macrophages by the glycosylphosphatidylinositols of Plasmodium falciparum: cell signaling receptors, glycosylphosphatidylinositol (GPI) structural requirement, and regulation of GPI activity. J Biol Chem 280 :8606–8616.

    • Search Google Scholar
    • Export Citation
  • 24

    Lu Z, Serghides L, Patel SN, Degousee N, Rubin BB, Krishnegowda G, Gowda DC, Karin M, Kain KC, 2006. Disruption of JNK2 decreases the cytokine response to Plasmodium falciparum glycosylphosphatidylinositol in vitro and confers protection in a cerebral malaria model. J Immunol 177 :6344–6352.

    • Search Google Scholar
    • Export Citation
  • 25

    Morgan E, Varro R, Sepulveda H, Ember JA, Apgar J, Wilson J, Lowe L, Chen R, Shivraj L, Agadir A, Campos R, Ernst D, Gaur A, 2004. Cytometric bead array: a multiplexed assay platform with applications in various areas of biology. Clin Immunol 110 :252–266.

    • Search Google Scholar
    • Export Citation
  • 26

    Christensen M, Su AW, Snyder RW, Greco A, Lipschutz JH, Madaio MP, 2006. Simvastatin protection against acute immune-mediated glomerulonephritis in mice. Kidney Int 69 :457–463.

    • Search Google Scholar
    • Export Citation
  • 27

    Mach F, 2004. Statins as immunomodulatory agents. Circulation 109 :II15–II17.

  • 28

    Kobbe R, Schreiber N, May J, Jacobs T, 2008. Simvastatin treatment shows no effect on the incidence of cerebral malaria or parasitemia during experimental malaria. Antimicrob Agents Chemother 52 :1583–1584.

    • Search Google Scholar
    • Export Citation
  • 29

    Bienvenu AL, Picot S, 2008. Statins alone are ineffective in cerebral malaria but potentiate artesunate. Antimicrob Agents Chemother 52 :4203–4204.

    • Search Google Scholar
    • Export Citation
  • 30

    Vigario AM, Belnoue E, Gruner AC, Mauduit M, Kayibanda M, Deschemin JC, Marussig M, Snounou G, Mazier D, Gresser I, Renia L, 2007. Recombinant human IFN-alpha inhibits cerebral malaria and reduces parasite burden in mice. J Immunol 178 :6416–6425.

    • Search Google Scholar
    • Export Citation
  • 31

    Day NP, Hien TT, Schollaardt T, Loc PP, Chuong LV, Chau TT, Mai NT, Phu NH, Sinh DX, White NJ, Ho M, 1999. The prognostic and pathophysiologic role of pro- and antiinflammatory cytokines in severe malaria. J Infect Dis 180 :1288–1297.

    • Search Google Scholar
    • Export Citation
  • 32

    Grau GE, Frei K, Piguet PF, Fontana A, Heremans H, Billiau A, Vassalli P, Lambert PH, 1990. Interleukin 6 production in experimental cerebral malaria: modulation by anticytokine antibodies and possible role in hypergammaglobulinemia. J Exp Med 172 :1505–1508.

    • Search Google Scholar
    • Export Citation
  • 33

    Romano M, Diomede L, Sironi M, Massimiliano L, Sottocorno M, Polentarutti N, Guglielmotti A, Albani D, Bruno A, Fruscella P, Salmona M, Vecchi A, Pinza M, Mantovani A, 2000. Inhibition of monocyte chemotactic protein-1 synthesis by statins. Lab Invest 80 :1095–1100.

    • Search Google Scholar
    • Export Citation
  • 34

    Tsuchiya A, Nagotani S, Hayashi T, Deguchi K, Sehara Y, Yamashita T, Zhang H, Lukic V, Kamiya T, Abe K, 2007. Macrophage infiltration, lectin-like oxidized-LDL receptor-1, and monocyte chemoattractant protein-1 are reduced by chronic HMG-CoA reductase inhibition. Curr Neurovasc Res 4 :268–273.

    • Search Google Scholar
    • Export Citation
  • 35

    Rallidis LS, Hamodraka ES, Fountoulaki K, Moustogiannis G, Zolindaki MG, Kremastinos DT, 2008. Simvastatin exerts its anti-inflammatory effect in hypercholesterolaemic patients by decreasing the serum levels of monocyte chemoattractant protein-1. Int J Cardiol 124 :271–272.

    • Search Google Scholar
    • Export Citation
  • 36

    Tanimoto A, Murata Y, Wang KY, Tsutsui M, Kohno K, Sasaguri Y, 2008. Monocyte chemoattractant protein-1 expression is enhanced by granulocyte-macrophage colony-stimulating factor via Jak2-Stat5 signaling and inhibited by atorvastatin in human monocytic U937 cells. J Biol Chem 283 :4643–4651.

    • Search Google Scholar
    • Export Citation
  • 37

    de Kossodo S, Grau GE, 1993. Profiles of cytokine production in relation with susceptibility to cerebral malaria. J Immunol 151 :4811–4820.

    • Search Google Scholar
    • Export Citation
  • 38

    Grau GE, Fajardo LF, Piguet PF, Allet B, Lambert PH, Vassalli P, 1987. Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria. Science 237 :1210–1212.

    • Search Google Scholar
    • Export Citation
  • 39

    Grau GE, Taylor TE, Molyneux ME, Wirima JJ, Vassalli P, Hommel M, Lambert PH, 1989. Tumor necrosis factor and disease severity in children with falciparum malaria. N Engl J Med 320 :1586–1591.

    • Search Google Scholar
    • Export Citation
  • 40

    Kwiatkowski D, Hill AV, Sambou I, Twumasi P, Castracane J, Manogue KR, Cerami A, Brewster DR, Greenwood BM, 1990. TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria. Lancet 336 :1201–1204.

    • Search Google Scholar
    • Export Citation
  • 41

    Grellier P, Valentin A, Millerioux V, Schrevel J, Rigomier D, 1994. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors lovastatin and simvastatin inhibit in vitro development of Plasmodium falciparum and babesia divergens in human erythrocytes. Antimicrob Agents Chemother 38 :1144–1148.

    • Search Google Scholar
    • Export Citation
  • 42

    Pradines B, Torrentino-Madamet M, Fontaine A, Henry M, Baret E, Mosnier J, Briolant S, Fusai T, Rogier C, 2007. Atorvastatin is 10-fold more active in vitro than other statins againstPlasmodium falciparum. Antimicrob Agents Chemother 51 :2654–2655.

    • Search Google Scholar
    • Export Citation
  • 43

    Niessner A, Steiner S, Speidl WS, Pleiner J, Seidinger D, Maurer G, Goronzy JJ, Weyand CM, Kopp CW, Huber K, Wolzt M, Wojta J, 2006. Simvastatin suppresses endotoxin-induced upregulation of toll-like receptors 4 and 2 in vivo. Atherosclerosis 189 :408–413.

    • Search Google Scholar
    • Export Citation
  • 44

    Methe H, Kim JO, Kofler S, Nabauer M, Weis M, 2005. Statins decrease toll-like receptor 4 expression and downstream signaling in human CD14+ monocytes. Arterioscler Thromb Vasc Biol 25 :1439–1445.

    • Search Google Scholar
    • Export Citation
  • 45

    Foldes G, von Haehling S, Okonko DO, Jankowska EA, Poole-Wilson PA, Anker SD, 2008. Fluvastatin reduces increased blood monocyte toll-like receptor 4 expression in whole blood from patients with chronic heart failure. Int J Cardiol 124 :80–85.

    • Search Google Scholar
    • Export Citation
  • 46

    Yilmaz A, Reiss C, Weng A, Cicha I, Stumpf C, Steinkasserer A, Daniel WG, Garlichs CD, 2006. Differential effects of statins on relevant functions of human monocyte-derived dendritic cells. J Leukoc Biol 79 :529–538.

    • Search Google Scholar
    • Export Citation
  • 47

    Sun D, Fernandes G, 2003. Lovastatin inhibits bone marrow-derived dendritic cell maturation and upregulates proinflammatory cytokine production. Cell Immunol 223 :52–62.

    • Search Google Scholar
    • Export Citation
  • 48

    Kiener PA, Davis PM, Murray JL, Youssef S, Rankin BM, Kowala M, 2001. Stimulation of inflammatory responses in vitro and in vivo by lipophilic HMG-CoA reductase inhibitors. Int Immunopharmacol 1 :105–118.

    • Search Google Scholar
    • Export Citation

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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

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  • 1 Institute of Medical Science, and Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; McLaughlin-Rotman Centre for Global Health, McLaughlin Centre for Molecular Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania; Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada

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.

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