Allergen-induced peribronchial fibrosis and mucus production mediated by IκB kinase β-dependent genes in airway epithelium

Abstract

In response to inflammation or injury, airway epithelial cells express inducible genes that may contribute to allergen-induced airway remodeling. To determine the contribution of epithelial cell NF-κB activation to the remodeling response, we generated CC10-Cre^tg /Ikkβ^Δ/Δ mice in which NF-κB signaling through IκB kinase β (IKKβ) is selectively ablated in the airway epithelium by conditional Cre-recombinase expression from the Clara cell (CC10) promoter. Repetitive ovalbumin challenge of mice deficient in airway epithelial IKKβ prevented nuclear translocation of the RelA NF-κB subunit only in airway epithelial cells, resulting in significantly lower peribronchial fibrosis in CC10-Cre^tg /Ikkβ^Δ/Δ mice compared with littermate controls as assessed by peribronchial trichrome staining and total lung collagen content. Levels of airway mucus, airway eosinophils, and peribronchial CD4⁺ cells in ovalbumin-challenged mice were also reduced significantly upon airway epithelial Ikkβ ablation. The diminished inflammatory response was associated with reduced expression of NF-κB-regulated chemokines, including eotaxin-1 and thymus- and activation-regulated chemokine, which attract eosinophils and Th2 cells, respectively, into the airway. The number of peribronchial cells expressing TGF-β1, as well as TGF-β1 amounts in bronchoalveolar lavage, were also significantly reduced in mice deficient in airway epithelium IKKβ. Overall, these studies show an important role for NF-κB regulated genes in airway epithelium in allergen-induced airway remodeling, including peribronchial fibrosis and mucus production.