Simvastatin suppresses endotoxin-induced upregulation of toll-like receptors 4 and 2 in vivo.
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-alpha 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.
Niessner
Alexander
A
Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. alexander.niessner@meduniwien.ac.at
Steiner
Sabine
S
Speidl
Walter S
WS
Pleiner
Johannes
J
Seidinger
Daniela
D
Maurer
Gerald
G
Goronzy
Jörg J
JJ
Weyand
Cornelia M
CM
Kopp
Christoph W
CW
Huber
Kurt
K
Wolzt
Michael
M
Wojta
Johann
J
D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D019446:Endotoxemia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D005500:Follow-Up Studies; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D007275:Injections, Intravenous; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics*; D012016:Reference Values; D019821:Simvastatin / Q000008:administration & dosage / Q000627:therapeutic use*; D051195:Toll-Like Receptor 2 / Q000187:drug effects / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000235:genetics*; D014158:Transcription, Genetic; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D019821:Simvastatin