Cooperative effects of Th2 cytokines and allergen on normal and asthmatic bronchial epithelial cells
Cooperative effects of Th2 cytokines and allergen on normal and asthmatic bronchial epithelial cells
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DOI：
10.4049/jimmunol.169.1.407
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发表时间：
2002-07-01
影响因子：
4.4
通讯作者：
Davies, DE
中科院分区：
文献类型：
--
作者：
Lordan, JL;Bucchieri, F;Davies, DE
在致敏个体中，接触屋尘螨 (Der p) 等过敏原会导致 Th2 极化并释放细胞因子，包括 IL-4 和 IL-13。由于 Der p 提取物也对上皮细胞有直接影响，因此我们假设过敏原通过促进过敏性哮喘中支气管上皮介质的释放来增强 Th2 细胞因子的作用。为了检验我们的假设，从正常和特应性哮喘受试者的支气管刷中培养原代支气管上皮培养物。 RT-PCR 显示，每种培养物均表达 IL-4Rα、常见 γ 链、IL-13Rα(1) 以及 IL-13Rα(2)，后者对 IL-13 信号传导负向调节； FACS分析证实IL-13Rα(2)蛋白表达。将上皮培养物暴露于 Der p 提取物、TNF-α、IL-4 或 IL-13 会增强 GM-CSF 和 IL-8 的释放，而皮质类固醇可以部分抑制这种释放。将上皮培养物同时暴露于 IL-4 或 IL-13 以及 Der p 导致细胞因子释放的进一步增加，这至少是相加的。 TNF-a 以及 IL-4、IL-13 和 Der p 的组合也可增加 TGF-α 的释放；然而，这种刺激仅在哮喘来源的培养物中才有意义。这些数据表明，在过敏环境中，Th2细胞因子和过敏原有可能通过对支气管上皮细胞因子释放的协同作用来维持气道炎症。我们的新发现是，IL-4、IL-13 和过敏原可增强 TGF-a 的释放，TGF-a 是表皮生长因子受体的配体，可刺激成纤维细胞增殖和杯状细胞分化，这提供了过敏原暴露、Th2 细胞因子和哮喘气道重塑之间的潜在联系。
In sensitized individuals, exposure to allergens such as Dermatophagoides pteronyssinus (Der p) causes Th2 polarization and release of cytokines, including IL-4 and IL-13. Because Der p extracts also have direct effects on epithelial cells, we hypothesized that allergen augments the effects of Th2 cytokines by promoting mediator release from the bronchial epithelium in allergic asthma. To test our hypothesis, primary bronchial epithelial cultures were grown from bronchial brushings of normal and atopic asthmatic subjects. RT-PCR showed that each culture expressed IL-4Ralpha, common gamma-chain, and IL-13Ralpha(1), as well as IL-13Ralpha(2), which negatively regulates IL-13 signaling; FACS analysis confirmed IL-13Ralpha(2) protein expression. Exposure of epithelial cultures to either Der p extracts, TNF-alpha, IL-4, or IL-13 enhanced GM-CSF and IL-8 release, and this was partially suppressible by corticosteroids. Simultaneous exposure of the epithelial cultures to IL-4 or IL-13 together with Der p resulted in a further increase in cytokine release, which was at least additive. Release of TGF-alpha was also increased by TNF-a and combinations of IL-4, IL-13, and Der p; however, this stimulation was only significant in the asthma-derived cultures. These data suggest that, in an allergic environment, Th2 cytokines and allergen have the potential to sustain airway inflammation through a cooperative effect on cytokine release by the bronchial epithelium. Our novel finding that IL-4, IL-13, and allergen enhance release of TGF-a, a ligand for the epidermal growth factor receptor that stimulates fibroblast proliferation and goblet cell differentiation, provides a potential link between allergen exposure, Th2 cytokines, and airway remodelling in asthma.