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Simvastatin inhibits the pro-inflammatory and pro-thrombotic effects of IL-17 and TNFα on endothelial cells
  1. Arnaud Hot,
  2. Vanina Lenief,
  3. Fabien Lavocat,
  4. Pierre Miossec
  1. Department of Immunology and Rheumatology and the Hospices Civils de Lyon mixed research unit, Hospital Edouard Herriot, Lyon, France

Abstract

Background Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, known as statins, are widely used for primary and secondary prevention of coronary artery atherosclerosis. Besides its lipid lowering properties, simvastatin has various anti-inflammatory effects.

Objectives The aim of this study was to assess whether simvastatin modulates the effects of IL-17, an emerging actor in atherosclerosis.

Methods The effect of simvastatin was assessed in HUVEC cells treated by IL-17 (100 ng/ml) alone or combined with TNFα (1 ng/ml), with or without mevalonate, a specific inhibitor of simvastatin. The effect of simvastatin on IL-17-induced cytokine or chemokine expression was assessed at the mRNA level using qRT-PCR or protein level by ELISA. Its effect on the IL-17-induced pro-thrombotic state and cell invasion was assessed using a lumiaggregometer and a matrigel assay, respectively.

Results Simvastatin decreased IL-17-induced IL-6, IL-8, CX3CL-1, RANTES mRNA and CX3CL-1 and CCL-20 production. Simvastatin restored the level of IL-33 mRNA which was decreased by IL-17. Simvastatin reduced the expression of IL-17-induced pro-thrombotic genes such as tissue factor. Simvastatin restored the level of platelet aggregation to normal levels.

Simvastatin enhanced the expression of CD39 and thrombomodulin mRNA initially reduced by IL-17 and TNFα combination. Simvastatin suppressed IL-17-induced EC invasion. All these effects were reversed by the addition of mevalonate. Finally, simvastatin had an additive effect with infliximab to decrease the effect of the combination of IL-17 and TNFα on IL-6 mRNA expression.

Conclusion These results indicate that simvastatin inhibits the pro-inflammatory, thrombotic and pro-aggregation effects of IL-17 on vessels. They provide a new understanding of the beneficial effects of statins in blood vessel inflammation.

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