Mechanisms of persistent NF-kappa B activity in the bronchi of an animal model of asthma

F Bureau, S Delhalle, G Bonizzi, L Fiévez, S Dogné, N Kirschvink, A Vanderplasschen, M P Merville, V Bours, P Lekeux

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)5822-30
Number of pages9
JournalJournal of immunology
Volume165
Issue number10
DOIs
Publication statusPublished - 15 Nov 2000

Keywords

  • Airway Obstruction/immunology
  • Animals
  • Asthma/immunology
  • Bronchi/immunology
  • Bronchoalveolar Lavage Fluid/cytology
  • Cell Death
  • Cell Survival
  • Cells, Cultured
  • DNA-Binding Proteins/antagonists & inhibitors
  • Dimerization
  • Disease Models, Animal
  • Granulocytes/metabolism
  • Horse Diseases/immunology
  • Horses
  • I-kappa B Proteins
  • Immune Sera/pharmacology
  • Interleukin-1/immunology
  • Leukocyte Count
  • NF-kappa B/antagonists & inhibitors
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha/immunology

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