IL-13-induced proliferation of airway epithelial cells: mediation by intracellular growth factor mobilization and ADAM17
IL-13-induced proliferation of airway epithelial cells: mediation by intracellular growth factor mobilization and ADAM17
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DOI：
10.1186/1465-9921-8-51
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发表时间：
2007-07-09
影响因子：
5.8
通讯作者：
Martin, Linda D.
中科院分区：
文献类型：
--
作者：
Booth, Brian W.;Sandifer, Tracy;Martin, Linda D.
背景：多效性细胞因子白细胞介素（IL）-13在过敏性和炎症性疾病中具有显著特征。在过敏性哮喘中，IL-13被公认为是气道炎症和组织重塑的诱导剂。我们先前证明IL-13诱导人支气管上皮细胞释放转化生长因子-α（TGF-α），这些细胞的增殖由该生长因子的自分泌/旁分泌作用介导。TGF α作为一个完整的膜蛋白存在，需要蛋白水解加工到其成熟的形式，与解整合素和金属蛋白酶（ADAM）17负责这种处理在各种tissues.Methods：在这项研究中，正常人支气管上皮细胞（NHBE）生长在空气/液体界面（ALI）培养被用来检查IL-13诱导释放TGF α和细胞增殖的机制。结果：IL-13可诱导NHBE细胞增殖，并以ADAM 17依赖的方式诱导TGF α的释放;然而，这种IL-13诱导的增殖似乎不仅仅是由ADAM 17激活引起的。相反，IL-13诱导TGF α表达的位置从NHBE细胞的细胞内到顶端区域的变化。顶端区域也被发现是一个网站的重要ADAM 17的表达，甚至在IL-13 stimulation.Conclusion：从这项研究的结果表明，ADAM 17介导的IL-13诱导的NHBE细胞增殖和TGF α脱落。此外，他们提供了第一个实施例，其中细胞因子（IL-13）诱导生长因子的细胞内表达模式的变化，明显诱导TGF α的细胞内储存重新分布到NHBE细胞的顶端区域，其中ADAM 17的表达显著。因此，IL-13诱导的、ADAM 17介导的TGF α释放以及随后的上皮细胞增殖可能导致上皮肥大以及与过敏性哮喘中的气道重塑相关的其他特征。
Background: The pleiotrophic cytokine interleukin (IL)-13 features prominently in allergic and inflammatory diseases. In allergic asthma, IL-13 is well established as an inducer of airway inflammation and tissue remodeling. We demonstrated previously that IL-13 induces release of transforming growth factor-alpha (TGF alpha) from human bronchial epithelial cells, with proliferation of these cells mediated by the autocrine/paracrine action of this growth factor. TGFa exists as an integral membrane protein and requires proteolytic processing to its mature form, with a disintegrin and metalloproteinase ( ADAM) 17 responsible for this processing in a variety of tissues.Methods: In this study, normal human bronchial epithelial (NHBE) cells grown in air/liquid interface (ALI) culture were used to examine the mechanisms whereby IL-13 induces release of TGFa and cellular proliferation. Inhibitors and antisense RNA were used to examine the role of ADAM17 in these processes, while IL-13-induced changes in the intracellular expression of TGFa and ADAM17 were visualized by confocal microscopy.Results: IL-13 was found to induce proliferation of NHBE cells, and release of TGF alpha, in an ADAM17-dependent manner; however, this IL-13-induced proliferation did not appear to result solely from ADAM17 activation. Rather, IL-13 induced a change in the location of TGFa expression from intracellular to apical regions of the NHBE cells. The apical region was also found to be a site of significant ADAM17 expression, even prior to IL-13 stimulation.Conclusion: Results from this study indicate that ADAM17 mediates IL-13-induced proliferation and TGF alpha shedding in NHBE cells. Furthermore, they provide the first example wherein a cytokine ( IL-13) induces a change in the intracellular expression pattern of a growth factor, apparently inducing redistribution of intracellular stores of TGF alpha to the apical region of NHBE cells where expression of ADAM17 is prominent. Thus, IL-13-induced, ADAM17-mediated release of TGF alpha, and subsequent epithelial cell proliferation, could contribute to the epithelial hypertrophy, as well as other features, associated with airway remodeling in allergic asthma.