Booth Brian W, Sandifer Tracy, Martin Erika L, Martin Linda D
Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA.
Respir Res. 2007 Jul 9;8(1):51. doi: 10.1186/1465-9921-8-51.
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 (TGFalpha) from human bronchial epithelial cells, with proliferation of these cells mediated by the autocrine/paracrine action of this growth factor. TGFalpha 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.
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 TGFalpha 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 TGFalpha and ADAM17 were visualized by confocal microscopy.
IL-13 was found to induce proliferation of NHBE cells, and release of TGFalpha, 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 TGFalpha 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.
Results from this study indicate that ADAM17 mediates IL-13-induced proliferation and TGFalpha 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 TGFalpha to the apical region of NHBE cells where expression of ADAM17 is prominent. Thus, IL-13-induced, ADAM17-mediated release of TGFalpha, and subsequent epithelial cell proliferation, could contribute to the epithelial hypertrophy, as well as other features, associated with airway remodeling in allergic asthma.
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起重要作用。在过敏性哮喘中，IL-13作为气道炎症和组织重塑的诱导因子已得到充分证实。我们先前证明，IL-13可诱导人支气管上皮细胞释放转化生长因子-α（TGFα），这些细胞的增殖由该生长因子的自分泌/旁分泌作用介导。TGFα以整合膜蛋白形式存在，需要蛋白水解加工成成熟形式，在多种组织中，金属蛋白酶解聚素（ADAM）17负责这种加工。
在本研究中，使用在气液界面（ALI）培养中生长的正常人支气管上皮（NHBE）细胞来研究IL-13诱导TGFα释放和细胞增殖的机制。使用抑制剂和反义RNA来研究ADAM17在这些过程中的作用，而通过共聚焦显微镜观察IL-13诱导的TGFα和ADAM17细胞内表达变化。
发现IL-13以ADAM17依赖的方式诱导NHBE细胞增殖和TGFα释放；然而，这种IL-13诱导的增殖似乎并非仅由ADAM17激活所致。相反，IL-13诱导了TGFα表达位置从NHBE细胞的细胞内区域向顶端区域的变化。即使在IL-13刺激之前，顶端区域也是ADAM17显著表达的部位。
本研究结果表明，ADAM17介导IL-13诱导的NHBE细胞增殖和TGFα脱落。此外，它们提供了第一个例子，即细胞因子（IL-13）诱导生长因子的细胞内表达模式发生变化，显然诱导TGFα细胞内储存重新分布到ADAM17表达突出的NHBE细胞顶端区域。因此，IL-13诱导的、ADAM17介导的TGFα释放以及随后的上皮细胞增殖，可能导致与过敏性哮喘气道重塑相关的上皮肥大以及其他特征。
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