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 language | English |
---|---|
Pages (from-to) | 5822-30 |
Number of pages | 9 |
Journal | Journal of immunology |
Volume | 165 |
Issue number | 10 |
DOIs | |
Publication status | Published - 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