Allergen-induced peribronchial fibrosis and mucus production mediated by IkappaB kinase beta-dependent genes in airway epithelium.
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-kappaB activation to the remodeling response, we generated CC10-Cre(tg)/Ikkbeta(delta/delta) mice in which NF-kappaB signaling through IkappaB kinase beta (IKKbeta) 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 IKKbeta prevented nuclear translocation of the RelA NF-kappaB subunit only in airway epithelial cells, resulting in significantly lower peribronchial fibrosis in CC10-Cre(tg)/Ikkbeta(delta/delta) 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 Ikkbeta ablation. The diminished inflammatory response was associated with reduced expression of NF-kappaB-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-beta1, as well as TGF-beta1 amounts in bronchoalveolar lavage, were also significantly reduced in mice deficient in airway epithelium IKKbeta. Overall, these studies show an important role for NF-kappaB regulated genes in airway epithelium in allergen-induced airway remodeling, including peribronchial fibrosis and mucus production.
Broide
David H
DH
Department of Medicine, Laboratory of Gene Regulation and Signal Transduction, University of California at San Diego, La Jolla, CA 92093, USA. dbroide@ucsd.edu
Lawrence
Toby
T
Doherty
Taylor
T
Cho
Jae Youn
JY
Miller
Marina
M
McElwain
Kirsti
K
McElwain
Shauna
S
Karin
Michael
M
D021581:Active Transport, Cell Nucleus; D000485:Allergens / Q000276:immunology*; D000818:Animals; D001982:Bronchial Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004804:Eosinophils / Q000166:cytology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis / Q000139:chemically induced* / Q000378:metabolism; D017353:Gene Deletion; D005838:Genotype; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007958:Leukocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009093:Mucus / Q000378:metabolism*; D009130:Muscle, Smooth / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010047:Ovalbumin / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics
D000485:Allergens; D016207:Cytokines; D016328:NF-kappa B; D010047:Ovalbumin; D051550:I-kappa B Kinase