Eosinophil-epithelial cell interactions stimulate the production of MUC5AC mucin and profibrotic cytokines involved in airway tissue remodeling

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To elucidate the role of eosinophils in tissue remodeling of chronic rhinosinusitis, eosinophil-epithelial interactions were examined by the co-culture of airway epithelial (NCI-H292) cells with the eosinophilic cell line EoL-1 or with human blood eosinophils.Eosinophil-epithelial interactions stimulated the secretion of MUC5AC, PDGF, VEGF, TGF-beta and IL-8 in culture supernatants. The EGFR tyrosine kinase inhibitor AG1478 inhibited the co-culture-induced secretion of MUC5AC, PDGF, VEGF, and IL-8. Neutralizing antibodies directed against TGF-alpha or amphiregulin and pan-metalloprotease inhibitor GM6001 inhibited the co-culture-induced secretion of MUC5AC and amphiregulin from the co-cultured NCI-H292 cells. These results indicate that eosinophil-epithelial interactions stimulate tissue remodeling induced by MUC5AC mucin, PDGF and VEGF, probably mediated by metalloprotease-dependent EGFR transactivation via amphiregulin and TGF-alpha released from the epithelial cells.