Inhibition of monocyte chemotactic protein-1 sysnthesis by statins

Maria Romano, Luisa Diomede, Marina Sironi, Lucia Massimiliano, Marcello Sottocorno, Nadia Polentarutti, Angelo Guglielmotti, Diego Albani, Alessandra Bruno, Paolo Fruscella, Mario Salmona, Annunciata Vecchi, Mario Pinza, Alberto Mantovani

Research output: Contribution to journalArticlepeer-review

Abstract

The beneficial effects of statins on the reduction of cardiovascular events has been partly attributed to their anti- inflammatory properties. In the complex of the different pathogenetic events leading to atherosclerosis, recent data suggest a central role of monocyte chemotactic protein-1 (MCP-1), because mice knock-out for MCP-1 or its receptor CC-chemokine receptor 2 were considerably resistant to plaque formation. In this study we investigated the effect of different statins on in vitro and in vivo production of MCP-1. Lovastatin and simvastatin caused a dose-dependent inhibition of MCP-1 production in peripheral blood mononuclear cells exposed to lipopolysaccharide or inactivated Streptococcus hemoliticus and in human endothelial cells exposed to interleukin-1β. The addition of mevalonate overrode the inhibitory effect of statins indicating that mevalonate-derived products are important for chemokine production. The in vivo anti-inflammatory effect of statins was investigated using the mouse air-pouch model of local inflammation. Lovastatin and pravastatin were orally administered to mice according to a treatment schedule that significantly inhibited the hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity without affecting total blood cholesterol. At the dose of 10 mg/kg, lovastatin and pravastatin reduced by approximately 50% the lipopolysaccharide-induced leukocytes recruitment and the exudate MCP-1 production. In conclusion, statins, by inhibiting mevalonate-derived products, reduced both in vitro and in vivo the production of chemokines involved in leukocyte migration, and this effect is unrelated to their cholesterol-lowering action.

Original languageEnglish
Pages (from-to)1095-1100
Number of pages6
JournalLaboratory Investigation
Volume80
Issue number7
Publication statusPublished - Jul 2000

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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