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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.
Publication Date: 2000-11-09 PubMed ID: 11067942DOI: 10.4049/jimmunol.165.10.5822Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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This research article focuses on studying the sustained activation of NF-kappaB, a crucial protein involved in inflammatory responses, in the airways of horses with spontaneous asthma. The authors find that this prolonged activation, contrary to usual cellular responses, is influenced by granulocytes (a type of immune cells) and specific inflammatory signals, IL-1beta and TNF-alpha, which also regulate a key NF-kappaB inhibitor, IkappaB-beta.
Research Context and Aim
- The article centers around NF-kappaB, a protein that induces many inflammatory responses within cells, including the production of its inhibitor, IkappaB-alpha. Usually, this initiates a transient response. However, in the context of asthma, the inflammatory gene expression facilitated by NF-kappaB remains persistent, even without allergen presence.
- The aim of the paper is to understand the mechanisms that sustain NF-kappaB activity in the bronchi (airways) of asthmatic animals. The authors utilize bronchial brushing samples (BBSs) from asthma-affected horses as their model system.
Research Findings and Methodology
- Through their investigation, they find high NF-kappaB activity in both granulocytic (involving granulocytes, a type of immune cells) and non-granulocytic BBS cells.
- The activity of NF-kappaB was found to be strongly correlated to the percentage of granulocytes. NF-kappaB activity ceased only after these granulocytes have died.
- The authors managed to suppress NF-kappaB activity before granulocyte death by adding neutralizing antibodies to IL-1beta and TNF-alpha (inflammatory mediators) together to the culture medium.
- IkappaB-beta was the major NF-kappaB inhibitor found in these BBSs, unlike IkappaB-alpha which usually regulates NF-kappaB. Interestingly, IkappaB-beta’s expression was not regulated by NF-kappaB.
- The authors saw low levels of IkappaB-beta in the BBSs from diseased horses, which substantially increased after the addition of neutralizing antibodies against IL-1beta and TNF-alpha.
Conclusion and Implications
- Overall, the results suggest that the sustained activation of NF-kappaB in the airways of asthmatic horses is driven primarily by granulocytes and mediated by the inflammatory regulators IL-1beta and TNF-alpha.
- Furthermore, an imbalance between excessive IL-1beta- and TNF-alpha-mediated IkappaB-beta degradation and its low-level synthesis might be preventing NF-kappaB deactivation before the death of granulocytes in asthmatic airways.
- These findings provide key insights into the mechanistic aspects of chronic inflammation in asthma and can guide future research for potential therapeutic interventions for asthma.
Cite This Article
APA
Bureau F, Delhalle S, Bonizzi G, Fiu00e9vez L, Dognu00e9 S, Kirschvink N, Vanderplasschen A, Merville MP, Bours V, Lekeux P.
(2000).
Mechanisms of persistent NF-kappa B activity in the bronchi of an animal model of asthma.
J Immunol, 165(10), 5822-5830.
https://doi.org/10.4049/jimmunol.165.10.5822 Publication
Researcher Affiliations
- 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.
MeSH Terms
- Airway Obstruction / immunology
- Airway Obstruction / metabolism
- Airway Obstruction / pathology
- Airway Obstruction / veterinary
- Animals
- Asthma / immunology
- Asthma / metabolism
- Asthma / pathology
- Asthma / veterinary
- Bronchi / immunology
- Bronchi / metabolism
- Bronchi / pathology
- Bronchoalveolar Lavage Fluid / cytology
- Cell Death
- Cell Survival
- Cells, Cultured
- DNA-Binding Proteins / antagonists & inhibitors
- DNA-Binding Proteins / metabolism
- DNA-Binding Proteins / pharmacology
- Dimerization
- Disease Models, Animal
- Granulocytes / metabolism
- Granulocytes / pathology
- Horse Diseases / immunology
- Horse Diseases / metabolism
- Horse Diseases / pathology
- Horses
- I-kappa B Proteins
- Immune Sera / pharmacology
- Interleukin-1 / immunology
- Leukocyte Count
- NF-kappa B / antagonists & inhibitors
- NF-kappa B / metabolism
- Transcription Factor RelA
- Tumor Necrosis Factor-alpha / immunology
Citations
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