IL-17A acts via p38 MAPK to increase stability of TNF-β-induced IL-8 mRNA in human ASM
IL-17A acts via p38 MAPK to increase stability of TNF-β-induced IL-8 mRNA in human ASM
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DOI：
10.1152/ajplung.00367.2005
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发表时间：
2006-06-01
影响因子：
4.9
通讯作者：
Ammit, AJ
中科院分区：
文献类型：
--
作者：
Henness, S;van Thoor, E;Ammit, AJ
人气道平滑肌（ASM）在哮喘中起免疫调节作用。最近，IL-17 A在哮喘中越来越受到关注，在哮喘气道中发现其水平升高，并在气道嗜酸性粒细胞中发挥重要作用。IL-17 A主要通过驻留气道结构细胞诱导细胞因子间接发挥其中性粒细胞协调作用。在此，我们进行了体外研究，以表明虽然IL-17 A不诱导CXC趋化因子IL-8从ASM细胞分泌，但IL-17 A以浓度和时间依赖性方式显著增强TNF-α诱导的IL-8蛋白分泌和基因表达（P < 0.05）。在IL-17 A存在下，与TNF-α孵育24小时后产生的IL-8蛋白水平增强2.7倍，并且条件培养基显著增强体外中性粒细胞趋化性。由于IL-17 A对NF-κ B的活性没有影响，NF-κ B是IL-8基因表达的关键转录调节因子，因此我们研究了IL-17 A是否在转录后水平起作用。我们发现IL-17 A显著增强TNF-α诱导的IL-8 mRNA稳定性。有趣的是，这种增强的稳定性通过p38 MAPK依赖性途径发生。当细胞用p38 MAPK抑制剂SB 203580预处理时，IL-8 mRNA转录物的衰减速度明显加快（- 0.05763 +/- 0.01964，t（1/2）= 12.0 h），与溶剂相比（-0.01030 +/-0.007963，t（1/2）= 67.3h）[结果表示为衰减常数（平均值+/- SE）和半衰期（t（1/2），h）：P < 0.05]。总的来说，这些结果表明，IL-17 A放大了ASM细胞的合成功能，通过p38 MAPK依赖性转录后途径发挥作用，以增加TNF-α诱导的ASM细胞分泌强效中性粒细胞趋化因子IL-8。
Human airway smooth muscle (ASM) plays an immunomodulatory role in asthma. Recently, IL-17A has become of increasing interest in asthma, being found at elevated levels in asthmatic airways and emerging as playing an important role in airway neutrophilia. IL-17A predominantly exerts its neutrophil orchestrating role indirectly via the induction of cytokines by resident airway structural cells. Here, we perform an in vitro study to show that although IL-17A did not induce secretion of the CXC chemokine IL-8 from ASM cells, IL-17A significantly potentiates TNF-alpha-induced IL-8 protein secretion and gene expression in a concentration-and time-dependent manner (P < 0.05). Levels of IL-8 protein produced after 24 h of incubation with TNF-alpha were enhanced 2.7-fold in the presence of IL-17A, and conditioned media significantly enhanced neutrophil chemotaxis in vitro. As IL-17A had no effect on the activity of NF-kappa B, a key transcriptional regulator of IL-8 gene expression, we then examined whether IL-17A acts at the posttranscriptional level. We found that IL-17A significantly augmented TNF-alpha-induced IL-8 mRNA stability. Interestingly, this enhanced stability occurred via a p38 MAPK-dependent pathway. The decay of IL-8 mRNA transcripts proceeded at a significantly faster rate when cells were pretreated with the p38 MAPK inhibitor SB203580 ( - 0.05763 +/- 0.01964, t(1/2) = 12.0 h), compared with vehicle ( - 0.01030 +/- 0.007963, t(1/2) = 67.3 h) [ results are expressed as decay constant ( means +/- SE) and half- life (t(1/2) in h): P < 0.05]. Collectively, these results demonstrate that IL-17A amplifies the synthetic function of ASM cells, acting via a p38 MAPK-dependent posttranscriptional pathway to augment TNF-alpha-induced secretion of the potent neutrophil chemoattractant IL-8 from ASM cells.