Simvastatin inhibits interleukin-6 release in human monocytes stimulated by C-reactive protein and lipopolysaccharide.
BACKGROUND
The accumulating evidence suggests that C-reactive protein (CRP) may have direct inflammatory effects on the vascular wall and that statin therapy may have important non-lipid anti-inflammatory effects confirmed by decreasing serum inflammatory markers, such as CRP. However, the effect of simvastatin on interleukin-6 (IL-6) release in cultured human monocytes was not investigated. DESIGN A prospective, human monocyte culture, simvastatin intervention study.


METHODS
Monocytes were isolated from blood of healthy volunteers by the Ficoll density gradient and stimulated by broad concentrations of CRP (1-20 microg/ml) and lipopolysaccharide (LPS, 1-10 ng/ml) at indicated time points (0, 2, 4, 8, 16 and 24 h). Also 10-8-10-6 mol/l simvastatin was coincubated with cells in the presence of CRP and LPS. Measurements of IL-6 were performed from supernatants of cultured medium in duplicate, using a commercial assay kit.


RESULTS
CRP and LPS induced the rapid release of IL-6, with significantly elevated levels in cultured supernatants at 4 h in the CRP group and at 2 h in the LPS group. The effects of CRP and LPS on IL-6 release of monocytes were dose and time dependent. A greater than 11-fold increase of IL-6 in the CRP group (20 microg/ml) and a greater than 26-fold increase in the LPS group (10 ng/ml) were observed at 24 h compared with the control group (945.7+/-98.3 pg/ml compared with 94.3+/-12.4 pg/ml and 1720.4+/-690.1 pg/ml compared with 70.1+/-16.7 pg/ml, P<0.001, respectively). However, 10-8-10-6 mol/l simvastatin inhibited significantly the production of IL-6 in monocytes stimulated by CRP and LPS in a dose-dependent manner, with the maximal inhibiting effect at a concentration of 10-6 mol/l (945.7+/-98.3 pg/ml compared with 180.9+/-31.2 pg/ml and 1720.4+/-690.1 pg/ml compared with 824.0+/-206.2 pg/ml, P<0.001 respectively).


CONCLUSIONS
CRP and LPS could induce IL-6 release in human monocytes and simvastatin could inhibit this response in a dose-dependent manner, which may provide an insight into the mechanisms of anti-inflammatory or anti-atherosclerotic actions of simvastatin.
Li
Jian-Jun
JJ
Department of Cardiology, Renmin Hospital, Wuhan University School of Medicine, 238 JieFang Road, Wuhan 430060, People's Republic of China. lijnjn@yahoo.com.cn
Chen
Xue-Jun
XJ
D002097:C-Reactive Protein / Q000494:pharmacology; D002478:Cells, Cultured; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000378:metabolism*; D011446:Prospective Studies; D019821:Simvastatin / Q000494:pharmacology*; D018709:Statistics, Nonparametric
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6; D008070:Lipopolysaccharides; D002097:C-Reactive Protein; D019821:Simvastatin