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首页> 外文期刊>Clinical and experimental allergy : >Cysteinyl-leukotrienes induce vascular endothelial growth factor production in human monocytes and bronchial smooth muscle cells.
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Cysteinyl-leukotrienes induce vascular endothelial growth factor production in human monocytes and bronchial smooth muscle cells.

机译：半胱氨酰白三烯诱导人单核细胞和支气管平滑肌细胞中血管内皮生长因子的产生。

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BACKGROUND: Cysteinyl leukotrienes (cysLTs) are suggested to be implicated in the process of airway remodelling in asthma. OBJECTIVE: We investigated the potential for cysLTs to modulate vascular endothelial growth factor (VEGF) expression, a growth factor involved in the angiogenesis of airway remodelling. METHODS: VEGF mRNA and protein were quantified by real-time PCR and ELISA, respectively. VEGF promoter activation was assessed using luciferase gene-tagged promoter constructs. RESULTS: We found that LTD(4) induction of VEGF in human monocytes and bronchial smooth muscle cells is cysLT1 dependent. Stimulation of HEK293 cells stably expressing cysLT1 or cysLT2 with cysLTs showed a concentration-dependent activation of the VEGF promoter and a time-dependent increase in VEGF mRNA and protein. For the cysLT1-mediated response, mutations of hypoxia-induced factor-1 (HIF-1) sites failed to reduce cysLT-induced VEGF promoter activation and 5' deletions showed that the proximal region containing one AP-1 and four specificity protein 1 (Sp1) sites was necessary. Pretreatment with inhibitors of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), but not p38, and an overexpression of dominant negative forms of c-Jun, c-Fos or Ras suggested the implication of mitogen-activated protein kinases and AP-1. Mutation of the AP-1-binding element failed to prevent VEGF transactivation suggesting that AP-1 might not act directly on the promoter. Moreover, inhibition of Sp1-dependent transcription by mithramycin completely inhibited VEGF promoter transactivation and VEGF mRNA expression by LTD(4) . Finally, mutations of Sp1 binding elements prevented VEGF promoter transactivation. CONCLUSION AND CLINICAL RELEVANCE: Our data indicate for the first time that cysLTs can transcriptionally activate VEGF production via cysLT1 receptors, with the involvement of JNK, ERK, the AP-1 complex and Sp1. These findings suggest that cysLTs may be important in the angiogenic process of airway remodelling and potentially provide a previously unknown benefit of using cysLT1 receptor antagonists in the prevention or treatment of airway remodelling in asthma.
机译：背景：半胱氨酸白三烯（cysLTs）被认为与哮喘的气道重塑过程有关。目的：我们研究了cysLTs调节血管内皮生长因子（VEGF）表达的潜力，VEGF是一种参与气道重塑血管生成的生长因子。方法：分别采用实时荧光定量PCR和ELISA法对VEGF mRNA和蛋白进行定量。使用荧光素酶基因标记的启动子构建体评估了VEGF启动子的激活。结果：我们发现LTD（4）诱导人单核细胞和支气管平滑肌细胞中的VEGF是cysLT1依赖的。用cysLTs刺激稳定表达cysLT1或cysLT2的HEK293细胞显示了VEGF启动子的浓度依赖性激活以及VEGF mRNA和蛋白的时间依赖性增加。对于cysLT1介导的反应，低氧诱导因子1（HIF-1）位点的突变未能减少cysLT诱导的VEGF启动子激活，并且5'缺失显示含有1个AP-1和4个特异性蛋白1的近端区域（ Sp1）网站是必要的。用c-Jun N末端激酶（JNK）和细胞外信号调节激酶（ERK）的抑制剂进行预处理，但不使用p38，并且c-Jun，c-Fos或Ras显性负性形式的过表达提示有丝分裂原的意义。活化的蛋白激酶和AP-1。 AP-1结合元件的突变未能阻止VEGF反式激活，表明AP-1可能不直接作用于启动子。此外，丝裂霉素对Sp1依赖性转录的抑制完全抑制了LTD（4）的VEGF启动子反式激活和VEGF mRNA的表达。最后，Sp1结合元件的突变阻止了VEGF启动子的反式激活。结论和临床意义：我们的数据首次表明cysLTs可以通过cysLT1受体在JNK，ERK，AP-1复合物和Sp1的参与下转录激活VEGF的产生。这些发现表明，cysLTs在气道重塑的血管生成过程中可能很重要，并可能提供使用cysLT1受体拮抗剂预防或治疗哮喘气道重塑的先前未知的益处。

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