title: Statin inhibition of Fc receptor-mediated phagocytosis by macrophages is modulated by cell activation and cholesterol.
abstract: OBJECTIVE
  An inflammatory response to altered lipoproteins that accumulate in the arterial wall is a major component of the pathogenesis of atherosclerosis. Statins reduce plasma levels of low-density lipoprotein (LDL) and are effective treatments for atherosclerosis. It is hypothesized that they also modulate inflammation. The aim of this study was to examine whether lovastatin inhibits macrophage inflammatory processes and clarify its mechanism of action.
  
  
  RESULTS
  We examined the effects of statins on phagocytosis of antibody-coated red blood cells by cultured human monocytes and mouse peritoneal macrophages. Lovastatin, simvastatin, and zaragozic acid, a squalene synthase inhibitor, blocked Fc receptor-mediated phagocytosis by cultured human monocytes and mouse peritoneal macrophages. The inhibitory effect of lovastatin on Fc receptor-mediated phagocytosis was prevented completely by addition of mevalonate, farnesyl pyrophosphate, LDL, or cholesterol to the culture medium. The inhibitory effect of zaragozic acid was reversed by addition of LDL, but not by the addition of geranylgeranyl pyrophosphate, to the medium. In addition, the effect of lovastatin on phagocytosis is a function of cell activation because treatment of cells with tumor necrosis factor-alpha or lipopolysaccharide prevented inhibition of phagocytosis by lovastatin.
  
  
  CONCLUSIONS
  The inhibition of Fc receptor-mediated phagocytosis of lovastatin is related to its effect on cholesterol biosynthesis rather than its effect on the formation of isoprenoids.
authors.affiliation: Department of Physiology, Columbia University College of Physician and Surgeons, 630 W 168th St, New York, NY 10032, USA. jdl5@columbia.edu
authors.forename: J D
authors.initials: JD
authors.lastname: Loike
authors.forename: D Y
authors.initials: DY
authors.lastname: Shabtai
authors.forename: R
authors.initials: R
authors.lastname: Neuhut
authors.forename: S
authors.initials: S
authors.lastname: Malitzky
authors.forename: E
authors.initials: E
authors.lastname: Lu
authors.forename: J
authors.initials: J
authors.lastname: Husemann
authors.forename: I J
authors.initials: IJ
authors.lastname: Goldberg
authors.forename: S C
authors.initials: SC
authors.lastname: Silverstein
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002478:Cells, Cultured; D002784:Cholesterol / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D005109:Extracellular Matrix / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008074:Lipoproteins / Q000737:chemistry / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology; D008262:Macrophage Activation / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology*; D010873:Pinocytosis / Q000187:drug effects; D011961:Receptors, Fc / Q000037:antagonists & inhibitors* / Q000502:physiology; D019821:Simvastatin / Q000494:pharmacology; D014233:Tricarboxylic Acids / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014617:Vacuoles / Q000378:metabolism
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D008074:Lipoproteins; D011961:Receptors, Fc; D014233:Tricarboxylic Acids; D014409:Tumor Necrosis Factor-alpha; C075117:squalestatin 1; D002784:Cholesterol; D008148:Lovastatin; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases