Down-regulation of E-cadherin in human bronchial epithelial cells leads to epidermal growth factor receptor-dependent Th2 cell-promoting activity
Down-regulation of E-cadherin in human bronchial epithelial cells leads to epidermal growth factor receptor-dependent Th2 cell-promoting activity
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DOI：
10.4049/jimmunol.178.12.7678
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发表时间：
2007-06-15
影响因子：
4.4
通讯作者：
Vellenga, Edo
中科院分区：
文献类型：
--
作者：
Heijink, Irene H.;Kies, P. Marcel;Vellenga, Edo
众所周知，气道上皮细胞是胸腺和活化调节趋化因子（TARC）的生产者，TARC是一种吸引Th 2细胞的趋化因子，可能在过敏性气道炎症的发展中发挥重要作用。然而，TARC在变态反应中上调的机制仍不清楚。在哮喘气道中，已经观察到细胞-细胞接触分子E-钙粘蛋白的表达丧失和上皮屏障功能降低，这可能是修复反应不足的结果。由于E-钙粘蛋白也抑制多种信号传导途径，我们研究了E-钙粘蛋白介导的细胞接触的破坏是否有助于上皮细胞的促过敏活性增加，例如，趋化因子TARC的产生。我们通过小干扰RNA下调支气管上皮细胞中的E-钙粘蛋白，并研究其对电阻、信号传导通路和TARC表达的影响（通过电细胞基质阻抗传感、免疫检测、免疫荧光染色和实时PCR）。E-cadherin的小干扰RNA沉默导致E-cadherin介导的连接丢失，表皮生长因子受体（EGFR）及其下游靶点MEK/ERK-1/2和p38 MAPK的磷酸化增强，最终导致TARC和胸腺基质淋巴细胞生成素表达上调。特异性抑制剂的使用表明，对TARC的影响是由MAPK通路的EGFR依赖性激活介导的。与TARC相反，Th 1/Treg细胞吸引趋化因子RANTES的表达不受E-钙粘蛋白下调的影响。总之，我们表明，E-钙粘蛋白介导的上皮细胞-细胞接触的损失，由破坏性刺激，过敏原，可能导致EGFR依赖性信号传导途径的抑制减少，随后诱导Th 2细胞吸引分子TARC。因此，细胞间上皮接触的破坏可能特异性地促进过敏性哮喘中Th 2细胞的募集。
Airway epithelial cells are well-known producers of thymus- and activation-regulated chemokine (TARC), a Th2 cell-attracting chemokine that may play an important role in the development of allergic airway inflammation. However, the mechanism responsible for up-regulation of TARC in allergy is still unknown. In the asthmatic airways, loss of expression of the cell-cell contact molecule E-cadherin and reduced epithelial barrier function has been observed, which may be the result of an inadequate repair response. Because E-cadherin also suppressed multiple signaling pathways, we studied whether disruption of E-cadherin-mediated cell contact may contribute to increased proallergic activity of epithelial cells, e.g., production of the chemokine TARC. We down-regulated E-cadherin in bronchial epithelial cells by small interference RNA and studied effects on electrical resistance, signaling pathways, and TARC expression (by electric cell-substrate impedance sensing, immunodetection, immunofluorescent staining, and real-time PCR). Small interference RNA silencing of E-cadherin resulted in loss of E-cadherin-mediated junctions, enhanced phosphorylation of epidermal growth factor receptor (EGFR), and the downstream targets MEK/ERK-1/2 and p38 MAPK, finally resulting in up-regulation of TARC as well as thymic stromal lymphopoietin expression. The use of specific inhibitors revealed that the effect on TARC is mediated by EGFR-dependent activation of the MAPK pathways. In contrast to TARC, expression of the Th1/Treg cell-attracting chemokine RANTES was unaffected by E-cadherin down-regulation. In summary, we show that loss of E-cadherin-mediated epithelial cell-cell contact by damaging stimuli, e.g., allergens, may result in reduced suppression of EGFR-dependent signaling pathways and subsequent induction of Th2 cell-attracting molecule TARC. Thus, disruption of intercellular epithelial contacts may specifically promote Th2 cell recruitment in allergic asthma.