Interleukin-1 beta (IL-1 beta) is a multipotent cytokine participating in a variety of cardiovascular diseases. In this study, we examined the effects of IL-1 beta on the expression of vascular endothelial cell growth factor (VEGF) and pursued the molecular mechanisms underlying this effect. Treatment of cultured neonatal rat cardiac myocytes with IL-1 beta increased the levels of VEGF mRNA in a time- and a concentration-dependent manner. These effects were completely abolished by SB203580 and SB202190 (p38 MAPK inhibitors) but not by PD98059 (MEK1 inhibitor), calphostin C (protein kinase C inhibitor), or genistein (tyrosine kinase inhibitor). While IL-1 beta phosphorylated c-Jun N-terminus protein kinase (JNK) rapidly and transiently, the effect of IL-1 beta on p38 mitogen-activated protein kinase (MAPK) was gradual and persistent. Transient transfection assays showed that IL-1 beta increases the transcription from the VEGF promoter. A series of 5;-deletion and site-specific mutation analyses indicated that IL-1 beta as well as overexpression of p38 MAPK and JNK activate VEGF promoter activity through two G+C-rich sequences located at -73 and -62. Electrophoretic mobility shift and supershift assays showed Sp1 and Sp3 proteins specifically bind to the G+C-rich sequences. The half-life of VEGF mRNA was significantly increased in cells treated with IL-1 beta. Together, these results indicate that IL-1 beta induces VEGF gene expression at both transcriptional and post-transcriptional levels, and IL-1 beta evokes p38 MAPK and JNK signalings, which in turn stimulate the transcription of the VEGF gene through Sp1-binding sites. These findings suggest the role of IL-1 beta as a cytokine inducing VEGF in cardiac myocytes, and imply that activation of stress-activated MAP kinases regulate Sp1 sites-dependent transcription.

译文

Interleukin-1 β (IL-1 β) 是一种参与多种心血管疾病的多能细胞因子。在这项研究中,我们研究了IL-1 β 对血管内皮细胞生长因子 (VEGF) 表达的影响,并探讨了这种作用的分子机制。用IL-1 β 处理培养的新生大鼠心肌细胞以时间和浓度依赖性方式增加VEGF mRNA的水平。SB203580和SB202190 (p38 MAPK抑制剂) 完全消除了这些作用,而PD98059 (MEK1抑制剂),钙磷蛋白C (蛋白激酶C抑制剂) 或染料木黄酮 (酪氨酸激酶抑制剂) 则没有。虽然快速且短暂地IL-1 β 磷酸化的c 6月N末端蛋白激酶 (JNK),但IL-1 β 对p38丝裂原活化蛋白激酶 (MAPK) 的影响是渐进且持续的。瞬时转染测定表明,IL-1 β 增加了来自VEGF启动子的转录。一系列5; 缺失和位点特异性突变分析表明,IL-1 β 以及p38mapk和JNK的过表达通过位于-73和-62的两个富含G C的序列激活VEGF启动子活性。电泳迁移率偏移和超移测定显示Sp1和Sp3蛋白与富含G C的序列特异性结合。在用IL-1 β 处理的细胞中,VEGF mRNA的半衰期显着增加。总之,这些结果表明IL-1 β 在转录和转录后水平上诱导VEGF基因表达,IL-1 β 引起p38mapk和JNK信号,这反过来通过Sp1-binding位点刺激VEGF基因的转录。这些发现表明IL-1 β 作为诱导心肌细胞中VEGF的细胞因子的作用,并暗示应激激活的MAP激酶的激活调节Sp1位点依赖性转录。

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