title: Mechanisms of persistent NF-kappa B activity in the bronchi of an animal model of asthma.
abstract: In most cells trans-activating NF-kappaB induces many inflammatory proteins as well as its own inhibitor, IkappaB-alpha, thus assuring a transient response upon stimulation. However, NF-kappaB-dependent inflammatory gene expression is persistent in asthmatic bronchi, even after allergen eviction. In the present report we used bronchial brushing samples (BBSs) from heaves-affected horses (a spontaneous model of asthma) to elucidate the mechanisms by which NF-kappaB activity is maintained in asthmatic airways. NF-kappaB activity was high in granulocytic and nongranulocytic BBS cells. However, NF-kappaB activity highly correlated to granulocyte percentage and was only abrogated after granulocytic death in cultured BBSs. Before granulocytic death, NF-kappaB activity was suppressed by simultaneous addition of neutralizing anti-IL-1beta and anti-TNF-alpha Abs to the medium of cultured BBSs. Surprisingly, IkappaB-beta, whose expression is not regulated by NF-kappaB, unlike IkappaB-alpha, was the most prominent NF-kappaB inhibitor found in BBSs. The amounts of IkappaB-beta were low in BBSs obtained from diseased horses, but drastically increased after addition of the neutralizing anti-IL-1beta and anti-TNF-alpha Abs. These results indicate that sustained NF-kappaB activation in asthmatic bronchi is driven by granulocytes and is mediated by IL-1beta and TNF-alpha. Moreover, an imbalance between high levels of IL-1beta- and TNF-alpha-mediated IkappaB-beta degradation and low levels of IkappaB-beta synthesis is likely to be the mechanism preventing NF-kappaB deactivation in asthmatic airways before granulocytic death.
authors.affiliation: Departments of Physiology and Immunology/Vaccinology, Faculty of Veterinary Medicine, and Laboratory of Medical Chemistry/Medical Oncology, Faculty of Medicine, University of Liege, Liege, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Bureau
authors.forename: S
authors.initials: S
authors.lastname: Delhalle
authors.forename: G
authors.initials: G
authors.lastname: Bonizzi
authors.forename: L
authors.initials: L
authors.lastname: Fiévez
authors.forename: S
authors.initials: S
authors.lastname: Dogné
authors.forename: N
authors.initials: N
authors.lastname: Kirschvink
authors.forename: A
authors.initials: A
authors.lastname: Vanderplasschen
authors.forename: M P
authors.initials: MP
authors.lastname: Merville
authors.forename: V
authors.initials: V
authors.lastname: Bours
authors.forename: P
authors.initials: P
authors.lastname: Lekeux
mesh_terms: D000402:Airway Obstruction / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000662:veterinary; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000662:veterinary; D001980:Bronchi / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016923:Cell Death; D002470:Cell Survival; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D019281:Dimerization; D004195:Disease Models, Animal; D006098:Granulocytes / Q000378:metabolism / Q000473:pathology; D006734:Horse Diseases / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006736:Horses; D020672:I-kappa B Proteins; D007106:Immune Sera / Q000494:pharmacology; D007375:Interleukin-1 / Q000276:immunology; D007958:Leukocyte Count; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D007106:Immune Sera; D007375:Interleukin-1; D016328:NF-kappa B; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha