Abstract
BackgroundThe 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-α (TGFα) from human bronchial epithelial cells, with proliferation of these cells mediated by the autocrine/paracrine action of this growth factor. TGFα 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.MethodsIn 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 TGFα 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 TGFα and ADAM17 were visualized by confocal microscopy.ResultsIL-13 was found to induce proliferation of NHBE cells, and release of TGFα, 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 TGFα 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.ConclusionResults from this study indicate that ADAM17 mediates IL-13-induced proliferation and TGFα 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 TGFα to the apical region of NHBE cells where expression of ADAM17 is prominent. Thus, IL-13-induced, ADAM17-mediated release of TGFα, and subsequent epithelial cell proliferation, could contribute to the epithelial hypertrophy, as well as other features, associated with airway remodeling in allergic asthma.
Highlights
The pleiotrophic cytokine interleukin (IL)-13 features prominently in allergic and inflammatory diseases
ADAM17 induced cellular proliferation as did IL-13 and transforming growth factor-α (TGFα) (Fig. 1b). These results indicate that normal human bronchial epithelial (NHBE) cells express TGFα on the extracellular membrane in a form that is amenable to proteolytic cleavage by ADAM17
This conclusion is supported by data demonstrating that the proliferation and growth factor shedding are inhibited by antisense oligonucleotides directed against ADAM17, while rhADAM17-induced proliferation of NHBE cells can be blocked with neutralizing anti-TGFα antibodies
Summary
The pleiotrophic cytokine interleukin (IL)-13 features prominently in allergic and inflammatory diseases. Cytokines and growth factors serve to enhance or resolve inflammation-induced changes in biological structures [4,5] Such a coordinated relationship between the cytokine interleukin-13 (IL-13) and the growth factor, transforming growth factor-α (TGFα), was demonstrated previously by our laboratory in normal human bronchial epithelial (NHBE) cells. IL-13 has been shown to play a role in the development of mucous cell hyperplasia [9,10,11], in activating matrix metalloproteinases [12], and in inducing expression of epithelium-derived growth factors (i.e. TGFα [6], TGFβ [13]) and chemokines (i.e. eotaxin [14], MCP-3 [15]) These released factors, in turn, affect neighboring epithelial cells as well as other cell types within the airway walls such as fibroblasts and smooth muscle cells [16]. While it is well documented that epithelial cells, including those of the airways, produce and release growth factors [17], the mechanism, or mechanisms, regulating cytokine-induced release of growth factors has not been fully elucidated
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