Mayer C, Gruber H J, Landl E M, Pailer S, Scharnagl H, Truschnig-Wilders M, März W
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, Austria.
Int J Clin Pharmacol Ther. 2007 Jun;45(6):319-27. doi: 10.5414/cpp45319.
It has been speculated that the reduction in vascular events by statins may not only be due to lowering of cholesterol, but also to the decrease in plasma C-reactive protein (CRP). In the present study we investigated the possibility that rosuvastatin directly affected CRP expression in stimulated human hepatocytes.
Interleukin 6 (IL-6) stimulated human hepatoma cells (Hep3B) and primary human hepatocytes (PHH) were incubated with various concentrations of rosuvastatin (0.3 - 1 microM) for 24 hours. CRP expression was determined using ELISA and quantitative real-time RT-PCR. The activation of STAT3 and C/EBP was investigated utilizing transcription factor assays (TransAM).
IL-6 increased CRP secretion by up to 5-fold in Hep3B and 6.6-fold in PHH. Rosuvastatin reduced CRP expression by 32% and 46% in Hep3B and PHH, respectively. IL-6 increased CRP mRNA up to 32-fold. At 1 microM, rosuvastatin reduced CRP mRNA by 73% compared to IL-6-stimulated cells. IL-6 activated the transcription factors STAT3 and C/EBP up to 2.6-fold and 2.2-fold, respectively. Rosuvastatin (1 microM) attenuated the activation of STAT3 and C/EBP by 48% and 54%, respectively.
Our results show a direct inhibitory effect of rosuvastatin on IL-6-induced expression of CRP in liver cells. Statins may lower CRP by inhibiting its production in the liver rather than by exerting systemic anti-inflammatory effects. The effects of rosuvastatin in reducing the levels of CRP in plasma may have clinical utility in addition to its effects on atherogenic lipoproteins.
有人推测他汀类药物降低血管事件的作用可能不仅归因于胆固醇水平的降低，还与血浆C反应蛋白（CRP）水平的下降有关。在本研究中，我们探讨了瑞舒伐他汀直接影响人肝细胞中CRP表达的可能性。
用不同浓度（0.3 - 1微摩尔）的瑞舒伐他汀处理白细胞介素6（IL-6）刺激的人肝癌细胞（Hep3B）和原代人肝细胞（PHH）24小时。采用酶联免疫吸附测定（ELISA）和定量实时逆转录聚合酶链反应（RT-PCR）检测CRP表达。利用转录因子分析（TransAM）研究信号转导和转录激活因子3（STAT3）及CCAAT增强子结合蛋白（C/EBP）的激活情况。
IL-6使Hep3B中CRP分泌增加高达5倍，在PHH中增加6.6倍。瑞舒伐他汀分别使Hep3B和PHH中的CRP表达降低32%和46%。IL-6使CRP信使核糖核酸（mRNA）增加高达32倍。与IL-6刺激的细胞相比，在1微摩尔浓度下，瑞舒伐他汀使CRP mRNA降低73%。IL-6分别使转录因子STAT3和C/EBP激活增加2.6倍和2.2倍。瑞舒伐他汀（1微摩尔）使STAT3和C/EBP的激活分别减弱48%和54%。
我们的结果显示瑞舒伐他汀对IL-6诱导的肝细胞中CRP表达有直接抑制作用。他汀类药物可能通过抑制肝脏中CRP的产生来降低其水平，而非通过发挥全身抗炎作用。瑞舒伐他汀降低血浆中CRP水平的作用，除了其对致动脉粥样硬化脂蛋白的作用外，可能还具有临床应用价值。
