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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1439.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Statins Decrease Toll-Like Receptor 4 Expression and Downstream Signaling in Human CD14⁺ Monocytes

Heiko Methe; Jong-Oh Kim; Sieglinde Kofler; Michael Nabauer; Michael Weis

From the Department of Cardiology, Ludwig-Maximilians-University, Munich, Germany.

Correspondence to Heiko Methe, MD, Harvard–MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 56-322, Cambridge, MA 02139. E-mail hmethe{at}mit.edu

Objective— Anti-inflammatory effects of statins contribute to their clinical benefit. Molecular mechanisms underlying these effects have not been well explored. Because statins attenuate lipopolysaccharide (LPS) responsiveness, we hypothesized that part of the pleiotropic effects are mediated through innate immunity.

Methods and Results— Toll-like receptor (TLR) 4 expression and downstream signaling in CD14⁺ monocytes after incubation with simvastatin and atorvastatin were quantified via flow-cytometry, quantitative RT-PCR, kinase assay, and enzyme-linked immunosorbent assay. Incubation with intermediates/ inhibitors of the mevalonate pathway was used to identify the mode of statin action. Statin incubation resulted in a dose-dependent reduction of TLR4 expression (53±7.6% reduction compared with untreated monocytes; P<0.005), transcript levels (68±6.3%; P<0.002), decreased IRAK phosphorylation (37±8.3%; P<0.05), and LPS-induced IL-6, IL-12, tumor necrosis factor (TNF)-, and B7-1 expression (P<0.05). Four weeks of treatment with atorvastatin significantly reduced TLR4 expression on circulating CD14⁺ monocytes by 36.2±4.2% (P<0.05). Effects of statins were reversed by mevalonate (P=0.57). Incubation with specific inhibitors of geranylgeranyltransferase (54±4.3%), farnesyltransferase (57±5.1%), or with clostridium-difficile toxin B (58±6.1%, P<0.01) imitated the statin effects. Whereas wortmannin and LY294002 inhibited the statin effect (P=0.27), incubation with a specific RhoA kinase inhibitor had no effect (P=0.57).

Conclusions— Statins influence TLR4 expression and signaling via inhibition of protein geranylgeranylation and farnesylation. These observations imply interactions with innate immunity as one pleiotropic mechanism.

Statin influences on expression and downstream signaling of Toll-like receptor 4 on CD14⁺ monocytes were assessed. Statins induced a dose-dependent downregulation of TLR4 with subsequent reduction in IRAK activity and cytokine and B7-1 expression. These effects were mediated via inhibition of protein geranylgeranylation and farnesylation. These observations imply a novel mechanism of pleiotropic statin effects.

Key Words: HMG-CoA reductase inhibitors • innate immune system • pleiotropic effects • Toll-like receptor

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