IL-13-induced proliferation of airway epithelial cells: mediation by intracellular growth factor mobilization and ADAM17

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.