Up-regulation of cysteinyl leukotriene 1 receptor by IL-13 enables human lung fibroblasts to respond to leukotriene C4 and produce eotaxin
Up-regulation of cysteinyl leukotriene 1 receptor by IL-13 enables human lung fibroblasts to respond to leukotriene C4 and produce eotaxin
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DOI：
10.4049/jimmunol.170.8.4290
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发表时间：
2003-04-15
影响因子：
4.4
通讯作者：
Fukuda, T
中科院分区：
文献类型：
--
作者：
Chibana, K;Ishii, Y;Fukuda, T
半胱氨酰白三烯（CysLTs）在嗜酸性粒细胞性气道炎症中起重要作用。除了对嗜酸性粒细胞的直接趋化作用外，还报告了间接作用。Eotaxin是一种主要由成纤维细胞产生的强效嗜酸性粒细胞特异性趋化因子。我们研究了CysLT是否通过成纤维细胞产生嗜酸性粒细胞活化趋化因子来增加嗜酸性粒细胞炎症。单独的白三烯（LT）C对人胎肺成纤维细胞（HFL-1）的嗜酸性粒细胞趋化因子产生无影响。然而，LTC 4刺激IL-13处理的成纤维细胞产生嗜酸性粒细胞趋化因子，从而间接诱导嗜酸性粒细胞隔离。未受刺激的成纤维细胞对LTC 4没有反应，但成纤维细胞与IL-13共孵育或预孵育改变了对LTC 4的反应。为了研究所涉及的机制，通过定量实时PCR和流式细胞术研究HFL-1中CysLT 1 R的表达。在未受刺激的HFL-1中，只有低水平的CysLT 1 R mRNA和无CysLT 1 R蛋白表达。与此相反，刺激与IL-13在10 ng/ml的浓度为24小时显着上调CysLT 1 R mRNA和蛋白质的表达在HFL-1。LTC 4和IL-13对Eotaxin产生的协同作用被CysLT 1 R拮抗剂普仑司特和孟鲁司特消除。这些发现表明，IL-13上调CysLT 1 R表达，这可能有助于LTC 4和IL-13对肺成纤维细胞产生嗜酸性粒细胞趋化因子的协同作用。在Th 2型细胞中，如在支气管哮喘中，成纤维细胞上的CysLT 1 R表达可能上调，从而使CysLTs有效地发挥作用并增加嗜酸性粒细胞炎症。
Cysteinyl leukotrienes (CysLTs) play an important role in eosinophilic airway inflammation. In addition to their direct chemotactic effects on eosinophils, indirect effects have been reported. Eotaxin is a potent eosinophil-specific chemotactic factor produced mainly by fibroblasts. We investigated whether CysLTs augment eosinophilic inflammation via eotaxin production by fibroblasts. Leukotriene (LT)C, alone had no effect on eotaxin-production by human fetal lung fibroblasts (HFL-1). However, LTC4 stimulated eotaxin production by IL-13-treated fibroblasts, thereby indirectly inducing eosinophil sequestration. Unstimulated fibroblasts did not respond to LTC4, but coincubation or preincubation of fibroblasts with IL-13 altered the response to LTC4. To examine the mechanism(s) involved, the expression of CysLT1R in HFL-1 was investigated by quantitative real-time PCR and flow cytometry. Only low levels of CysLT1R mRNA and no CysLT1R protein were expressed in unstimulated HFL-1. In contrast, stimulation with IL-13 at a concentration of 10 ng/ml for 24 h significantly up-regulated both CysLT1R mRNA and protein expression in HFL-1. The synergistic effect of LTC4 and IL-13 on eotaxin production was Abolished by CysLT1R antagonists pranlukast and montelukast. These findings suggest that IL-13 up-regulates CysLT1R expression, which may contribute to the synergistic effect of LTC4 and IL-13 on eotaxin production by lung fibroblasts. In the Th2 cytokine-rich milieu, such as that in bronchial asthma, CysLT1R expression on fibroblasts might be up-regulated, thereby allowing CysLTs to act effectively and increase eosinophilic inflammation.