Endothelin-1 induces interleukin-6 release via activation of the transcription factor NF-κB in human vascular smooth muscle cells
Endothelin-1 induces interleukin-6 release via activation of the transcription factor NF-κB in human vascular smooth muscle cells
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DOI：
10.1007/s003950050170
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发表时间：
2000-04-01
影响因子：
9.5
通讯作者：
Kranzhöfer, R
中科院分区：
文献类型：
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作者：
Browatzki, M;Schmidt, J;Kranzhöfer, R
强效血管收缩肽内皮素-1 (ET-1) 与动脉粥样硬化及其并发症的病理生理学有关。由于血管壁炎症是动脉粥样硬化的标志，本研究的目的是研究 ET-1 对人血管平滑肌细胞 (SMC) 细胞因子产生的影响，作为炎症细胞激活的标志。 ET-1 (100 pM - 1 muM) 以浓度依赖性方式刺激人血管 SMC 分泌白细胞介素 6 (IL-6)。 ET-A受体拮抗剂BQ-123(10μM)抑制IL-6释放，但ET-B受体拮抗剂BQ-788不抑制IL-6释放。 ET-1 还短暂地增加了 IL-6 mRNA，与翻译前水平的 IL-6 释放调节相一致。电泳迁移率变动分析表明，在 ET-1 刺激的人血管 SMC 中，促炎转录因子核因子 kappa B (NF-kappa B) 的激活具有时间和浓度依赖性。带有NF-κB结合位点的诱饵寡脱氧核苷酸在很大程度上抑制ET-1刺激的IL-6释放，这表明该转录因子对于ET-1引发的细胞因子产生起着关键作用。此外，抗氧化剂吡咯烷二硫代氨基甲酸酯（10 μM）抑制 ET-1 诱导的 IL-6 释放，表明活性氧参与 ET-1 信号传导。 ET-1刺激的IL-6分泌也被二亚苯基碘鎓（40μM）抑制，二亚苯基碘鎓是一种含黄酮酶（例如NADH/NADPH氧化酶）的抑制剂。结果证明 ET-1 能够在人血管 SMC 中诱导炎症反应。这些观察结果可能有助于更好地理解 ET-1 在动脉粥样硬化形成过程中血管壁炎症激活中的作用。
The potent vasoconstrictor peptide endothelin-1 (ET-1) has been implicated in the pathophysiology of atherosclerosis and its complications. Since inflammation of the vessel wall is a hallmark of atherosclerosis, the purpose of the present study was to investigate the influence of ET-1 on cytokine production in human vascular smooth muscle cells (SMC) as a marker of inflammatory cell activation. ET-1 (100 pM - 1 mu M) stimulated interleukin-6 (IL-6) secretion from human vascular SMC in a concentration-dependent manner. The ET-A-receptor antagonist BQ-123 (10 mu M), but not the ET-B-receptor antagonist BQ-788, inhibited IL-6 release. ET-1 also transiently increased IL-6 mRNA compatible with regulation of IL-6 release at the pretranslational level. Electrophoretic mobility shift assays demonstrated time- and concentration-dependent activation of the proinflammatory transcription factor nuclear factor-kappa B (NF-kappa B) in ET-1-stimulated human vascular SMC. A decoy oligodeoxynucleotide bearing the NF-kappa B binding site inhibited ET-l-stimulated IL-6 release to a great extent suggesting that this transcription factor plays a key role for cytokine production elicited by ET-1. Moreover, the antioxidant pyrrolidine dithiocarbamate (10 mu M) inhibited ET-1-induced IL-6 release indicating involvement of reactive oxygen species in ET-1 signaling. ET-1-stimulated IL-6 secretion was also suppressed by diphenylene iodonium (40 mu M), an inhibitor of flavon-containing enzymes such as NADH/NADPH oxidase. The results demonstrate the ability of ET-1 to induce an inflammatory response in human vascular SMC. These observations may contribute to a better understanding of the role of ET-1 in inflammatory activation of the vessel wall during atherogenesis.