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首页> 外文期刊>Clinical and experimental allergy : >Transforming growth factor-beta stimulates the expression of eotaxin/CC chemokine ligand 11 and its promoter activity through binding site for nuclear factor-kappaB in airway smooth muscle cells.
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Transforming growth factor-beta stimulates the expression of eotaxin/CC chemokine ligand 11 and its promoter activity through binding site for nuclear factor-kappaB in airway smooth muscle cells.

机译：转化生长因子-β通过气道平滑肌细胞中核因子-κB的结合位点刺激嗜酸性粒细胞趋化因子/ CC趋化因子配体11的表达及其启动子活性。

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BACKGROUND: Chemokines ligands of CCR3 including eotaxin/CC chemokine ligand 11 (CCL11) may contribute to the pathogenesis of asthma. These chemokines and a growth factor (TGF-beta) may be involved in the process of airway remodelling. OBJECTIVE: We analysed the effects of TGF-beta on the expression of CCR3 ligands in human airway smooth muscle (HASM) cells and investigated the mechanisms. METHODS: HASM cells were cultured and treated with TGF-beta and Th2 cytokines IL-4 or IL-13. Expression of mRNA was analysed by real-time PCR. Secretion of CCL11 into the culture medium was analysed by ELISA. Transcriptional regulation of CCL11 was analysed by luciferase assay using CCL11 promoter-luciferase reporter plasmids. RESULTS: IL-4 or IL-13 significantly up-regulated the expression of mRNAs for CCL11 and CCL26. TGF-beta alone did not increase the expression of chemokine mRNAs, but enhanced the induction of only CCL11 by IL-4 or IL-13 among CCR3 ligands. Activity of the CCL11 promoter was stimulated by IL-4, and this activity was enhanced by TGF-beta. Activation by IL-4 or IL-4 plus TGF-beta was lost by mutation of the binding site for signal transducers and activators of transcription-6 (STAT6) in the promoter. Cooperative activation by IL-4 and TGF-beta was inhibited by mutation of the binding site for nuclear factor-kappaB (NF-kappaB) in the promoter. Pretreatment with an inhibitor of NF-kappaB and glucocorticoid fluticasone propionate significantly inhibited the expression of CCL11 mRNA induced by IL-4 plus TGF-beta, indicating the importance of NF-kappaB in the cooperative activation of CCL11 transcription by TGF-beta and IL-4. CONCLUSION: These results indicate that Th2 cytokines and TGF-beta may contribute to the pathogenesis of asthma by stimulating expression of CCL11. The transcription factors STAT6 and NF-kappaB may play pivotal roles in this process.
机译：背景：CCR3的趋化因子配体包括嗜酸性粒细胞趋化因子/ CC趋化因子配体11（CCL11）可能与哮喘的发病机理有关。这些趋化因子和生长因子（TGF-beta）可能参与气道重塑的过程。目的：分析TGF-β对人气道平滑肌（HASM）细胞CCR3配体表达的影响，并探讨其机制。方法：培养HASM细胞并用TGF-β和Th2细胞因子IL-4或IL-13处理。通过实时PCR分析mRNA的表达。通过ELISA分析CCL11向培养基中的分泌。使用CCL11启动子-荧光素酶报告质粒通过荧光素酶测定法分析了CCL11的转录调控。结果：IL-4或IL-13显着上调了CCL11和CCL26的mRNA表达。单独的TGF-β不会增加趋化因子mRNA的表达，但会增强CCR3配体中IL-4或IL-13对CCL11的诱导作用。 IL-4刺激了CCL11启动子的活性，而TGF-β增强了该活性。 IL-4或IL-4和TGF-β的激活因启动子中信号转导子和转录激活子6（STAT6）的结合位点突变而丢失。 IL-4和TGF-β的协同激活被启动子中核因子-κB（NF-kappaB）结合位点的突变所抑制。用NF-κB抑制剂和丙酸氟替卡松丙酸酯预处理可显着抑制IL-4加TGF-β诱导的CCL11 mRNA的表达，表明NF-κB在TGF-β和IL-β协同激活CCL11转录中的重要性。 4。结论：这些结果表明Th2细胞因子和TGF-β可能通过刺激CCL11的表达促进哮喘的发病。转录因子STAT6和NF-κB在此过程中可能起关键作用。

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