IL-9 and IL-13 Induce Mucous Cell Metaplasia That Is Reduced by IFN-γ in a Bax-Mediated Pathway

Abstract

One of the major aspects of airway remodeling in asthma is the development of mucous cell metaplasia (MCM). The role of cytokines in the generation and resolution of MCM has been studied in mice and in isolated airway epithelial cells in culture. However, studies using organ cultures that keep the tubular structure of the airways intact and allow studies in the absence of inflammatory cells have not been reported. We established an organ culture system that replicates the allergen-induced MCM in mice and analyzed the role of Bax in the IFN-gamma-induced resolution of MCM. IL-9 or IL-13 induced MCM independently, but a combined IL-9/IL-13 treatment enhanced MCM synergistically. Addition of IFN-gamma at 0.1 ng/ml concentration further increased MCM to levels observed in allergen-exposed mice in vivo. However, MCM was reduced when explants were treated with 50 ng/ml IFN-gamma after MCM was established. While IL-9/IL-13 induced MCM in bronchioles microdissected from bax(+/+) and bax(-/-) mice to a similar extent, IFN-gamma treatment reduced MCM only in bronchioles from bax(+/+) but not in bax(-/-) bronchioles. Restoration of Bax expression in bax(-/-) bronchioles using an adenoviral expression system reduced IL-9/IL-13-induced MCM while MCM was similar in noninfected or adenoviral green fluorescent protein-infected bax(-/-) bronchioles. Furthermore, expressing Bax using an adenoviral expression system reduced allergen-induced MCM in mice. These studies show that allergen-induced MCM is a response to a combination of various cytokines at defined concentrations and that IFN-gamma requires Bax for the resolution of MCM.