Statins reduce interleukin-6-induced C-reactive protein in human hepatocytes - New evidence for direct antiinflammatory effects of statins
Statins reduce interleukin-6-induced C-reactive protein in human hepatocytes - New evidence for direct antiinflammatory effects of statins
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DOI：
10.1161/01.atv.0000163840.63685.0c
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发表时间：
2005-06-01
影响因子：
8.7
通讯作者：
Mach, F
中科院分区：
文献类型：
--
作者：
Arnaud, C;Burger, F;Mach, F
目的- C-反应蛋白（CRP）除了在确定心血管风险方面的预测作用外，还可能通过促炎特性发挥直接的促动脉粥样硬化作用。CRP主要由肝细胞对白细胞介素- 6 （IL- 6）产生，然后释放到体循环中。3-羟基- 3-甲基戊二酰(HMG)-辅酶A （CoA）还原酶抑制剂或他汀类药物可显著降低有或无冠状动脉疾病患者的心血管事件和死亡率，并降低人类血浆CRP水平。然而，他汀类药物降低血浆CRP水平的机制尚不清楚。方法和结果-在这项研究中，我们报道了他汀类药物限制人肝细胞中IL- 6诱导的CRP蛋白和RNA水平。这些作用被L-甲羟戊酸逆转，并被香叶基香叶基转移酶抑制剂模拟。IL- 6诱导的CRP生成需要IL- 6与其同源受体结合，从而导致转录因子STAT3的激活和磷酸化。我们提供的证据表明，他汀类药物可以减少肝细胞中IL- 6诱导的STAT3磷酸化。结论-这些结果表明，他汀类药物通过抑制蛋白香叶酰化直接减少肝细胞中IL- 6诱导的CRP生成。我们进一步证明他汀类药物通过抑制STAT3磷酸化起作用。这些发现为他汀类药物的直接抗炎特性提供了新的证据，并为其临床益处提供了新的机制见解。
Objectives - Besides its predictive role in determining cardiovascular risk, C- reactive protein ( CRP) may exert direct proatherogenic effects through proinflammatory properties. CRP is mainly produced by hepatocytes in response to interleukin- 6 ( IL- 6) and is then released into the systemic circulation. 3- hydroxy- 3- methylglutaryl ( HMG)- coenzyme A ( CoA) reductase inhibitors, or statins, significantly reduce cardiovascular events and mortality in patients with or without coronary artery disease and reduce plasma CRP levels in humans. However, the mechanism by which statins reduce plasma CRP levels remains unknown.Methods and Results - In this study, we report that statins limit both protein and RNA levels of IL- 6- induced CRP in human hepatocytes. These effects are reversed by L- mevalonate and mimicked by an inhibitor of the geranylgeranyltransferase. IL- 6 - induced CRP production requires the binding of IL- 6 to its cognate receptors, which results in activation and phosphorylation of the transcription factor STAT3. We provide evidence that statins reduce this IL- 6 - induced phosphorylation of STAT3 in hepatocytes.Conclusion - These results demonstrate that statins reduce IL- 6 - induced CRP production directly in hepatocytes via inhibition of protein geranylgeranylation. We further show that statins act via inhibition of STAT3 phosphorylation. These findings furnish new evidence for direct antiinflammatory properties of statins and provide new mechanistic insight into their clinical benefits.