IL-13 induces a bronchial epithelial phenotype that is profibrotic
- Author(s): Malavia, Nikita K.
- Mih, Justin D.
- Raub, Christopher B.
- Dinh, Bao T.
- George, Steven C.
- et al.
Published Web Locationhttps://doi.org/10.1186/1465-9921-9-27
Background: Inflammatory cytokines (e. g. IL-13) and mechanical perturbations (e. g. scrape injury) to the epithelium release profibrotic factors such as TGF-beta(2), which may, in turn, stimulate subepithelial fibrosis in asthma. We hypothesized that prolonged IL-13 exposure creates a plastic epithelial phenotype that is profibrotic through continuous secretion of soluble mediators at levels that stimulate subepithelial fibrosis. Methods: Normal human bronchial epithelial cells (NHBE) were treated with IL-13 (0, 0.1, 1, or 10 ng/ml) for 14 days (day 7 to day 21 following seeding) at an air-liquid interface during differentiation, and then withdrawn for 1 or 7 days. Pre-treated and untreated NHBE were cocultured for 3 days with normal human lung fibroblasts (NHLF) embedded in rat-tail collagen gels during days 22-25 or days 28-31. Results: IL-13 induced increasing levels of MUC5AC protein, and TGF-beta(2), while decreasing beta-Tubulin IV at day 22 and 28 in the NHBE. TGF-beta(2), soluble collagen in the media, salt soluble collagen in the matrix, and second harmonic generation (SHG) signal from fibrillar collagen in the matrix were elevated in the IL-13 pre-treated NHBE co-cultures at day 25, but not at day 31. A TGF-beta(2) neutralizing antibody reversed the increase in collagen content and SHG signal. Conclusion: Prolonged IL-13 exposure followed by withdrawal creates an epithelial phenotype, which continuously secretes TGF-beta(2) at levels that increase collagen secretion and alters the bulk optical properties of an underlying fibroblast-embedded collagen matrix. Extended withdrawal of IL-13 from the epithelium followed by co-culture does not stimulate fibrosis, indicating plasticity of the cultured airway epithelium and an ability to return to a baseline. Hence, IL-13 may contribute to subepithelial fibrosis in asthma by stimulating biologically significant TGF-beta(2) secretion from the airway epithelium.
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