doi: 10.1161/01.ATV.0000223146.16466.af
© 2006 American Heart Association, Inc.
Letters to the Editor |
Letter to the Editor
Modulation of Toll-Like Receptor Expression: A Further Effect of Statins?
Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil
To the Editor:
Inhibitors of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase (or statins) represent a family of chemically related molecules selected for their lipid-lowering effect. Statins are extensively used in medical practice, and large clinical trials have demonstrated that this class of lipid-lowering drugs greatly reduces cardiovascular-related morbidity and mortality in patients with and without coronary disease.1 However, benefits from statin therapy appear to exceed their lipid-lowering effect.
We have read with great interest the article by Methe and colleagues2 published in Arteriosclerosis, Thrombosis, and Vascular Biology. The investigators described that statin (simvastatin and atorvastatin) treatment reduces Toll-like receptor 4 (TLR4) surface expression on human monocytes in vivo and in vitro in a dose-dependent fashion. Although the mechanisms of immunomodulatory properties of statins have not been fully clarified, the authors make the interesting observation that the effects of statins on reduction of TLR4 surface expression were correlated with downregulation of IRAK-1 kinase activity and reduced expression of proinflammatory cytokines after stimulation with lipopolysaccharide (LPS), suggesting that expressional regulation of Toll-like receptors is controlled by proinflammatory cytokine production. In accordance, recently, Niessner and colleagues3 demonstrated that high-dose simvastatin pretreatment blunted TLR2 and TLR4 surface expression on monocytes in a human endotoxemia model. Moreover, the reduction of TLR expression also was associated with diminished tumor necrosis factor (TNF)-
and monocyte chemoattractant protein-1 (MCP-1) plasma levels. Altogether, these findings suggest that the effect of statins on TLR expression may reveal a potential mechanism for their beneficial statin effects not only in cardiovascular disease but also in sepsis.
In fact, a growing body of evidence indicates that TLRs may play a role in the pathophysiology of sepsis. There is evidence that early increase in TLR2 and TLR4 protein expression is correlated with high mortality, whereas blunting TLR expression correlated with improved long-term survival of septic mice.4 In this context, recently, we have demonstrated that TLR4-deficient mice are more resistant to polymicrobial sepsis induced by cecal ligation and puncture (CLP) murine model,5 suggesting that the TLR4 would be a potential target molecule for therapeutic intervention in sepsis. Interestingly, pretreatment with simvastatin results in profoundly improved survival in CLP sepsis model.6 Furthermore, mice pretreated with cerivastatin had significant reduction of mortality in a LPS-induced endotoxic shock model.7
In summary, the study of Methe and colleagues is another important addition to the growing literature describing the pleiotropic effects of statins, highlighting evidence that statins influence TLRs expression and signaling. Moreover, their findings reinforce that statins might be an additional potential agent in sepsis treatment.
References
1. Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation. 2000; 101: 207–213.
2. Methe H, Kim JO, Kofler S, Nabauer M, Weis M. Statins decrease Toll-like receptor 4 expression and downstream signaling in human CD14+ monocytes. Arterioscler Thromb Vasc Biol. 2005; 25: 1439–1445.
3. Niessner A, Steiner S, Speidl WS, Pleiner J, Seidinger D, Maurer G, Goronzy JJ, Weyand CM, Kopp CW, Huber K, Wolzt M, Wojta J. Simvastatin suppresses endotoxin-induced upregulation of toll-like receptors 4 and 2 in vivo. Atherosclerosis. In press.
4. Williams DL, Ha T, Li C, Kalbfleisch JH, Schweitzer J, Vogt W, Browder IW. Modulation of tissue Toll-like receptor 2 and 4 during the early phases of polymicrobial sepsis correlates with mortality. Crit Care Med. 2003; 31: 1808–1818.[CrossRef][Medline] [Order article via Infotrieve]
5. Alves-Filho JC, de Freitas A, Russo M, Cunha FQ. Toll-like receptor 4 signaling leads to neutrophil migration impairment in polymicrobial sepsis. Crit Care Med. 2006; 34: 461–470.[CrossRef][Medline] [Order article via Infotrieve]
6. Merx MW, Liehn EA, Janssens U, Lutticken R, Schrader J, Hanrath P, Weber C. HMG-CoA reductase inhibitor simvastatin profoundly improves survival in a murine model of sepsis. Circulation. 2004; 109: 2560–2565.
7. Ando H, Takamura T, Ota T, Nagai Y, Kobayashi K. Cerivastatin improves survival of mice with LPS-induced sepsis. J Pharmacol Exp Ther. 2000; 294: 1043–1046.
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