1. Opposite effects of simvastatin on the bactericidal and inflammatory response of macrophages to opsonized S. aureus
- Author
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Daniela Benati, Micol Ferro, Cosima T. Baldari, Franco Laghi Pasini, Maria Teresa Savino, Annalisa Nuccitelli, Cristina Ulivieri, and Ebe Schiavo
- Subjects
rho GTP-Binding Proteins ,Simvastatin ,Staphylococcus aureus ,statins ,macrophage ,phagocytosis ,proinflammatory cytokines ,signal transduction ,immunosuppression ,Phagocytosis ,Immunology ,Protein Prenylation ,Inflammation ,Context (language use) ,Fc receptors ,Oxidative burst ,Protein prenylation ,Ras superfamily GTpases ,Statins ,Actins ,Animals ,Cell Line ,Cytoskeleton ,Humans ,Inflammation Mediators ,Macrophages ,Membrane Microdomains ,Mice ,Microbial Viability ,Opsonin Proteins ,Receptors, IgG ,Respiratory Burst ,Signal Transduction ,ras Proteins ,Cell Biology ,Biology ,Proinflammatory cytokine ,medicine ,Immunology and Allergy ,Macrophage ,nutritional and metabolic diseases ,Respiratory burst ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,medicine.drug - Abstract
By impairing prenylation of Ras-related GTPases, simvastatin blocks phagocytosis and oxidative burst while enhancing production of proinflammatory mediators in human macrophages challenged with IgG-coated bacteria. 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 FcγR 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 FcγR 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.
- Published
- 2009