Abstract
Airway remodeling observed in chronic inflammatory diseases of the respiratory system is characterized by mucous cell hyperplasia, smooth muscle cell proliferation and subepithelial fibrosis. Interleukin (IL)-13 is a central mediator in the pathogenesis of inflammatory airway diseases playing a significant role in epithelial remodeling. In this study, we examined mechanisms through which IL-13 induces proliferation of normal human bronchial epithelial (NHBE) cells maintained in air/liquid interface culture in vitro, a model that allows for the maintenance of differentiated structure and function. It was found that IL-13-induced proliferation of NHBE cells is mediated by the autocrine/paracrine action of transforming growth factor-a (TGFa) that is produced by the epithelial cells and subsequently binds to the epidermal growth factor receptor (EGFR) on these cells. IL-13-induced release of TGFa involves the rapid mobilization of intracellular stores of TGFa to the apical cell surface, where membrane bound TGFa is cleaved by tumor necrosis factor-a converting enzyme (TACE), resulting in released growth factor. Both neutralizing anti-TGFa antibodies and the EGFR tyrosine kinase inhibitor AG1478 block IL-13-induced proliferation in concentration-dependent manners. Additionally, IL-13 induces the activation of the mitogen activated (MAP) kinase pathway and the phosphatidylinositol 3-kinase (PI3K) pathway, both of which are required for IL-13-induced proliferation. However, activation of the MAP kinase pathway by IL-13 does not appear to be TGFa mediated, as neutralizing anti-TGFa antibodies and EGFR tyrosine kinase inhibitors have little effect on IL-13-induced MAP kinase. PI3K was found to be involved in IL-13-induced release of TGFa as the specific inhibitor of PI3K, LY294002, blocks release of the growth factor. In summary, IL-13-induced proliferation of NHBE cells involves the intracellular redistribution and subsequent TACE-mediated release of TGFa, an event mediated by PI3K. This proliferation then involves the interaction of TGFa with the EGFR and requires activation of both the MAP kinase and the PI3K signaling cascades. These data establish a mechanistic framework for further study into the effects of IL-13 on bronchial epithelial cells as well as additional cell types that may interact with IL-13, or growth factors induced by this cytokine, in an in vivo setting.
|
