Simvastatin suppresses endotoxin-induced upregulation of toll-like receptors 4 and 2 in vivo

Abstract

In addition to lipid lowering effects, statins appear to have pleiotropic immunomodulatory properties. As they particularly affect monocyte functions, we tested the influence of statin treatment on the monocyte activating toll-like receptors (TLR) 4 and 2 in response to lipopolysaccharides (LPS) in vivo. In this double-blind, placebo-controlled study, 20 healthy, male subjects were randomized to receive either simvastatin (80 mg/day) or placebo for 4 days before intravenous LPS administration (20 IU/kg). Simvastatin did not influence the increase in TLR transcripts after LPS administration measured in mRNA isolated from whole blood by quantitative RT-PCR. In contrast, the parallel upregulation of TLR4 and TLR2 on the surface of monocytes determined by flow cytometry was attenuated by more than half after LPS challenge ( P < 0.02). Suppressed TLR4 and TLR2 expression was associated with diminished circulating concentrations of tumor necrosis factor-α and monocyte chemoattractant protein-1. In conclusion, high-dose simvastatin pretreatment blunted TLR4 and TLR2 expression on monocytes in a human endotoxemia model on a posttranscriptional level. This suppressive effect of statins on key receptors of the innate immunity which was associated with a reduction of effector cytokines reveals a potential mechanism for their beneficial effects in sepsis and cardiovascular disease.