Opposite effects of simvastatin on the bactericidal and inflammatory response of macrophages to opsonized S. aureus.
Besides lowering circulating cholesterol, statins act as immunomodulators. Although the effects of statins on lymphocyte activation and differentiation have been clearly defined, there is no consensus as to effects of these drugs on phagocytes. We have addressed the outcome of simvastatin treatment on the activation and effector function of human macrophages in the pathophysiologically relevant context of challenge with an opportunistic pathogen. We provide evidence that: simvastatin blocks the biological effects rapidly triggered by IgG-opsonized bacteria (phagocytosis and oxidative burst) while enhancing the delayed effects elicited by FcgammaR stimulation (production of proinflammatory mediators); these opposite effects of simvastatin result from enhancement of the JNK pathway and concomitant impairment of other signaling modules activated by FcgammaR engagement; and these activities are dependent on the capacity of simvastatin to block protein prenylation. The results provide novel mechanistic insight into the activities of statins on phagocytes and are of relevance to the assessment of potential side-effects in patients undergoing long-term hypocholesterolemic therapy.
Benati
Daniela
D
Department of Evolutionary Biology, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
Ferro
Micol
M
Savino
Maria Teresa
MT
Ulivieri
Cristina
C
Schiavo
Ebe
E
Nuccitelli
Annalisa
A
Pasini
Franco Laghi
FL
Baldari
Cosima T
CT
D000199:Actins / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000382:microbiology; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology*; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D050296:Microbial Viability / Q000187:drug effects*; D009895:Opsonin Proteins / Q000276:immunology*; D010587:Phagocytosis / Q000187:drug effects; D017368:Protein Prenylation / Q000187:drug effects; D017452:Receptors, IgG / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D018631:ras Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000199:Actins; D018836:Inflammation Mediators; D009895:Opsonin Proteins; D017452:Receptors, IgG; D019821:Simvastatin; D018631:ras Proteins; D020741:rho GTP-Binding Proteins