Induction of interleukin-6 expression by angiotensin II in rat vascular smooth muscle cells
Induction of interleukin-6 expression by angiotensin II in rat vascular smooth muscle cells
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DOI：
10.1161/01.hyp.34.1.118
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发表时间：
1999-07-01
期刊：
影响因子：
8.3
通讯作者：
Takeshita, A
中科院分区：
文献类型：
--
作者：
Funakoshi, Y;Ichiki, T;Takeshita, A
最近的研究表明，动脉粥样硬化是一种炎症过程，细胞因子在这一过程中发挥着重要作用。虽然血管紧张素II(Ang II)在动脉粥样硬化形成中起重要作用已被公认，但Ang II在细胞因子产生中的作用尚未被探讨。本研究探讨血管紧张素转换酶II(Ang II)对多功能促炎细胞因子白介素6(IL-6)在大鼠血管平滑肌细胞产生的影响。Ang II可显著增加IL-6mRNA和蛋白的表达，并呈剂量依赖关系(10(-10)~10(-6)mol/L)。血管紧张素Ⅱ诱导的IL-6mRNA表达在刺激后30分钟和12~24小时出现两个高峰。Ang II对IL-6释放和mRNA表达的影响可被Ang II 1型受体拮抗剂CV11974完全阻断，而Ang II 2型受体拮抗剂PD123319则无此作用。用BAPTA-AM螯合细胞内钙离子，用金雀异黄素抑制酪氨酸激酶，用PD98059抑制丝裂原活化蛋白激酶，可完全阻断Ang II的作用。然而，佛波酯或蛋白激酶C特异性抑制剂calphostin C可下调蛋白激酶C的表达，但不影响Ang II诱导的IL-6mRNA的表达。IL-6基因启动子的缺失和突变分析表明，cAMP反应元件：在Ang II诱导的IL-6基因表达中起重要作用。凝胶迁移率改变分析显示，Ang II可增加cAMP反应元件结合蛋白的表达。这些结果为进一步研究Ang II信号转导途径以及Ang II在血管炎症变化中的作用提供了新的思路。
Recent studies suggest that atherosclerosis is a kind of inflammatory process and that cytokine plays important roles in this process. Although it is generally accepted that angiotensin II (Ang II) plays an important-role in atherogenesis, the role of Ang II in cytokine production has not been explored. In this report, we investigated the effect of Ang II on the production of interleukin-6 (IL-6), which is a multifunctional proinflammatory cytokine in rat vascular smooth muscle cells. Ang II significantly increased the expression of IL-6 mRNA and protein in a dose-dependent manner (10(-10) to 10(-6) mol/L). The expression of IL-6 mRNA induced by Ang II showed 2 peaks at 30 minutes and 12 to 24 hours after stimulation. The effect of Ang II on IL-6 release and mRNA expression was completely blocked by an Ang II type 1 receptor antagonist, CV11974; however, an Ang II type 2 receptor antagonist, PD123319, showed no effect. Chelating of intracellular Ca2+ with BAPTA-AM, inhibition of tyrosine kinase with genistein, and inhibition of mitogen-activated protein kinase kinase with PD98059 completely abolished the effect of Ang II. However, downregulation of protein kinase C by pretreatment with a phorbol ester for 24 hows or a specific protein kinase C inhibitor, calphostin C, did not affect the Ang II-induced expression of IL-6 mRNA. Deletion and mutational analysis of IL-6 gene promoter showed that cAMP-responsive element: was important for Ang II-induced IL-6 gene expression. Gel mobility shift assay showed an;increase of cAMP-responsive element binding protein by Ang II. These results provide new insights into Ang II signaling and the role of Ang II,in the progression of inflammatory changes of blood vessels.