Human Eosinophils Induce Mucin Production in Airway Epithelial Cells Via Epidermal Growth Factor Receptor Activation

Abstract

Eosinophil recruitment and mucus hypersecretion are characteristic of asthmatic airway inflammation, but eosinophils have not been shown to induce mucin production. Because an epidermal growth factor receptor (EGFR) cascade induces MUC5AC mucin in airways, and because EGFR is up-regulated in asthmatic airways, we examined the effect of eosinophils on MUC5AC mucin production in NCI-H292 cells (a human airway epithelial cell line that produces mucins). Eosinophils were isolated from the peripheral blood of allergic patients, and their effects on MUC5AC mucin gene and protein synthesis were assessed using in situ hybridization and ELISAs. When IL-3 plus GM-CSF or IL-3 plus IL-5 were added to eosinophils cultured with NCI-H292 cells, MUC5AC mucin production increased; eosinophils or cytokines alone had no effect. Eosinophil supernatant obtained by culturing eosinophils with IL-3 plus GM-CSF or IL-3 plus IL-5 also increased MUC5AC synthesis in NCI-H292 cells, an effect that was prevented by selective EGFR inhibitors (AG1478, BIBX1522). Supernatant of activated eosinophils induced EGFR phosphorylation in NCI-H292 cells. Supernatant of activated eosinophils contained increased concentrations of TGF-α protein (an EGFR ligand) and induced up-regulation of TGF-α expression and release in NCI-H292 cells. A blocking Ab to TGF-α reduced activated eosinophil-induced MUC5AC synthesis in NCI-H292 cells. These results show that activated eosinophils induce mucin synthesis in human airway epithelial cells via EGFR activation, and they implicate TGF-α produced by eosinophils and epithelial cells in the EGFR activation that results in mucin production in human airway epithelium.

Chronic bronchitis sub-phenotype within COPD: inflammation in sputum and biopsies

“…Nevertheless, the present study shows that chronic bronchitis is related to eosinophils in biopsies and sputum. Increased numbers of eosinophils in sputum that have migrated through the epithelial layer may contribute to mucus hypersecretion through the action of transforming growth factor (TGF)-a [30] or by stimulating degranulation of mucus-producing cells through the release of inflammatory mediators, including cysteinyl leukotrienes [31]. Therefore, the present findings of a preferential distribution are in line with a role of eosinophils in mucus hypersecretion.…”

Chemokine Receptors in Asthma: Searching for the Correct Immune Targets

“…Thus, the mechanism linking chemokine receptor expression, leukocyte activation, and airway mucus overproduction together may be through an EGFR-mediated event in the epithelium. Perhaps chemokines mediate these airway events via induced release of EGFR ligands, such as heparin binding-EGF, from the infiltrating leukocytes facilitating goblet cell hyperplasia and/or mucus production as previously established (58,59), an idea supported by recent studies of another 7-transmembrane receptor, platelet activating factor receptor (60). This concept is summarized in Fig.…”

A3 Adenosine Receptor Signaling Contributes to Airway Inflammation and Mucus Production in Adenosine Deaminase-Deficient Mice

“…Results in the current study demonstrate that the mucus production in the airways of ADA Ϫ/Ϫ mice can be prevented by antagonism or removal of the A 3 R suggesting that A 3 R signaling is important for mucus metaplasia in this model. However, it is not clear at this stage whether the decrease in mucus production results from direct effects of A 3 R signaling on mucus-producing cells, or is an effect of preventing airway eosinophilia, which has been shown to be associated with mucus production (48,49). Determining the role of the A 3 R on mucus-producing cells will provide important new insight into how adenosine signaling can impact chronic lung disease.…”