1. ¹Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche "Mario Negri," Milan
2. ²Department of Immunology, Istituto di Ricerche Farmacologiche "Mario Negri," Milan
3. ³Angelini Ricerche SpA, Rome
4. ⁴Department of Biotechnology, University of Brescia, Brescia, Italy

Correspondence: Luisa Diomede, Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche "Mario Negri," Via Eritrea 62- 20157 Milano-Italy; Fax: 0039–2-3546277; E-mail: diomede@irfmn.mnegri.it

Received 30 March 2000.

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-1. 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.