FcεRI-mediated amphiregulin production by human mast cells increases mucin gene expression in epithelial cells

Abstract

Topical application of a glucocorticoid is now widely recognized as the first-line therapy for bronchial asthma. However, glucocorticoid treatment is largely ineffective in relation to overproduction of sputum and lung tissue remodeling. The purpose of the current study was to identify human mast cell (MC) products that are related to goblet cell hyperplasia. The FcepsilonRI-mediated gene expression profile of MCs was examined by using high-density oligonucleotide probe arrays and RT-PCR. Secretion of a protein, amphiregulin, by the MCs was measured by ELISA. Upregulation of mucin genes in NCI-H292 cells by amphiregulin was evaluated by real-time RT-PCR. The expression levels of amphiregulin on histological sections obtained from 40 subjects with asthma and 6 healthy control subjects were estimated by immunohistochemical staining, and the correlation with the number of goblet cells was studied. Amphiregulin was secreted by human MCs after aggregation of FcepsilonRI, and its expression was not inhibited by a glucocorticoid (dexamethasone). Amphiregulin upregulated mucin gene expression in airway epithelial cells. Upregulation of amphiregulin expression was observed in MCs of patients with asthma, but not normal control subjects. Furthermore, upregulation of amphiregulin in MCs significantly correlated with the extent of goblet cell hyperplasia in the mucosa of patients with bronchial asthma. These results suggest that after exposure to antigens, human MCs may induce sputum production via release of amphiregulin. Therefore, amphiregulin may be a new target molecule for treatment of overproduction of sputum in bronchial asthma.