Inhibition of Monocyte Chemotactic Protein-1 Synthesis by Statins

Abstract

SUMMARY: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. (Lab Invest 2000, 80:1095-1100.

HMG-CoA Reductase Inhibitor Simvastatin Profoundly Improves Survival in a Murine Model of Sepsis

“…23 Because mevalonate is the precursor not only of cholesterol but also of many other nonsteroidal isoprenoid products, HMG-CoA reductase inhibition might affect several other cellular functions. In this context, suppression of T-cell responses 24 reduced expression of class II major histocompatibility complexes on antigen-presenting cells, 12 and reduced chemokine synthesis in peripheral blood mononuclear cells 25 has been demonstrated. In addition, it was recently reported by Weitz-Schmidt et al 26 that several statins (including simvastatin) are capable of blocking the LFA-1-ICAM-1 interaction, providing a mevalonate and thus HMG-CoA reductase-independent pathway for anti-inflammatory and immunomodulatory statin actions.…”

Protective effect of simvastatin in the cyclophosphamide-induced hemohrragic cystitis in rats

“…Although no literature reports on the use of statins for the prevention and treatment of CH, there is increasing evidence to support the suggestion that simvastatin acts as a powerful antiinflammatory with a wide spectrum of effects [22][23][24] . The use of different statins in vivo and in vitro showed a decreased production of chemokines involved in leukocyte migration 25 . It has been also demonstrated that statin decreases the expression of cytokines 26 .…”

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

“…Simvastatin inhibits the production of MCP-1 by human ECs stimulated by C-reactive protein (CRP), interleukin-1␤ (IL-1␤), or lipopolysaccharide (LPS) in vitro (53), and both lovastatin and simvastatin decrease MCP-1 production in human peripheral monocytes (54,55). These effects are reversed with the addition of mevalonate (54).…”

“…Simvastatin inhibits the production of MCP-1 by human ECs stimulated by C-reactive protein (CRP), interleukin-1␤ (IL-1␤), or lipopolysaccharide (LPS) in vitro (53), and both lovastatin and simvastatin decrease MCP-1 production in human peripheral monocytes (54,55). These effects are reversed with the addition of mevalonate (54). Withdrawal of cerivastatin from pretreated vascular smooth muscle cells induces MCP-1 production, an effect that is replicated when these cells are coincubated with cerivastatin plus GGPP, which suggests that it occurs via geranylgeranylated proteins (56).…”