Atherosclerosis 189 (2006) 408–413 Simvastatin suppresses endotoxin-induced upregulation of toll-like receptors 4 and 2 in vivo Alexander Niessner a,d,∗ , Sabine Steiner b , Walter S. Speidl a , Johannes Pleiner c , Daniela Seidinger b , Gerald Maurer a ,J¨ org J. Goronzy d , Cornelia M. Weyand d , Christoph W. Kopp b , Kurt Huber e , Michael Wolzt c , Johann Wojta a a Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria b Department of Internal Medicine II, Division of Angiology, Medical University of Vienna, Austria c Department of Clinical Pharmacology, Medical University of Vienna, Austria d Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA e 3rd Department of Medicine, Cardiology and Emergency Medicine, Wilhelminenhospital, Vienna, Austria Received 19 November 2005; received in revised form 17 December 2005; accepted 21 December 2005 Available online 26 January 2006 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 lipopolysac- charides (LPS) in vivo. In this double-blind, placebo-controlled study, 20 healthy, male subjects were randomized to receive either simvastatin (80mg/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- 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. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Statins; Lipopolysaccharides; Innate immune system; Toll-like receptor 1. Introduction In clinical trials, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) not only reduced cardiovas- cular events [1,2] but also improved outcome in sepsis [3,4]. In addition to lipid lowering effects, statins appear to exhibit pleiotropic immunomodulatory and atheroprotective proper- ties such as reduction of vascular inflammation and plaque ∗ Corresponding author. Tel.: +43 1 40400 4614; fax: +43 1 4081148. E-mail address: alexander.niessner@meduniwien.ac.at (A. Niessner). stabilization [5,6]. In particular, effector pathways of mono- cytes/macrophages may be attenuated by statin treatment [5–9]. So far little is known about mechanisms responsible for these immunomodulatory effects. Toll-like receptors (TLRs) are critical for the induction of downstream effector functions in monocytes as consequence of recognizing pathogen-associated molecular patterns [10]. Beyond the particular importance of TLR4 in sepsis by recognizing lipopolysaccharides (LPS) in conjunction with CD14, emerging data support its contribution to atherosclero- sis: patients with coronary artery disease, particularly during 0021-9150/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2005.12.022