Interleukin-13 induces proliferation of human airway epithelial cells in vitro via a mechanism mediated by transforming growth factor-α
Interleukin-13 induces proliferation of human airway epithelial cells in vitro via a mechanism mediated by transforming growth factor-α
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DOI：
10.1165/ajrcmb.25.6.4659
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发表时间：
2001-12-01
影响因子：
6.4
通讯作者：
Martin, LD
中科院分区：
文献类型：
--
作者：
Booth, BW;Adler, KB;Martin, LD
哮喘患者中发生的气道重塑与上皮损伤和修复周期期间炎症介质和 Th2 细胞因子（尤其是白细胞介素 (IL)-13）的持续存在有关。在这项研究中，我们检测了 IL-13 对气液界面培养中分化良好的正常人支气管上皮 (NHBE) 细胞的影响。 [H-3]胸苷摄取和细胞计数反映，暴露 24 小时后，IL-13 诱导 NHBE 细胞增殖。 IL-13 的作用是通过表皮生长因子受体 (EGFR) 介导的，因为 EGFR 酪氨酸激酶抑制剂 AG1478 会减弱增殖。增殖似乎是由转化生长因子 (TGF)-α 介导的，TGF-α 是 EGFR 的有效配体，响应 IL-13 从 NHBE 细胞中快速释放。 TGF-α 的中和抗体，但不是针对其他潜在重要生长因子（EGF、肝素结合表皮生长因子样生长因子 [HB-EGF]、血小板衍生生长因子 [PDGF]）的抗体，抑制对 IL-13 的促有丝分裂反应。这项研究提供了第一个实验证据，证明 IL-13 在没有炎症细胞或其他细胞类型的情况下可以启动人气道上皮的增殖反应。结果与 IL-13 诱导上皮细胞释放 TGF-α 的机制一致，TGF-α 反过来通过自分泌/旁分泌型作用与 EGFR 结合，启动增殖。 IL-13 诱导的体内气道重塑可能涉及这种上皮驱动的反应。
Remodeling of the airways, as occurs in asthmatic patients, is associated with the continual presence of inflammatory mediators and Th2 cytokines, especially interleukin (IL)-13, during cycles of epithelial injury and repair. In this study, we examined the effect of IL-13 on well-differentiated normal human bronchial epithelial (NHBE) cells maintained in air-liquid interface culture. IL-13 induced proliferation of NHBE cells after 24 h exposure, as reflected by [H-3]thymidine uptake and cell counts. The effects of IL-13 were mediated through the epidermal growth factor receptor (EGFR), as proliferation was attenuated by AG1478, an EGFR tyrosine kinase inhibitor. Proliferation appeared to be mediated by transforming growth factor (TGF)-alpha, a potent ligand for EGFR, which was released rapidly from NHBE cells in response to IL-13. Neutralizing antibody to TGF-alpha, but not antibodies against other potentially important growth factors (EGF, heparin binding epidermal growth factor-like growth factor [HB-EGF], platelet-derived growth factor [PDGF]), inhibited the mitogenic response to IL-13. This study provides the first experimental evidence that IL-13 can initiate a proliferative response of human airway epithelium in the absence of inflammatory cells or other cell types. The results are consistent with a mechanism whereby IL-13 induces release of TGF-alpha from the epithelial cells, which in turn binds via an autocrine/paracrine-type action to the EGFR, initiating proliferation. IL-13-induced airway remodeling in vivo may involve this epithelium-driven response.