In most cells trans-activating NF-κB induces many inflammatory proteins as well as its own inhibitor, IκB-α, thus assuring a transient response upon stimulation. However, NF-κB-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-κB activity is maintained in asthmatic airways. NF-κB activity was high in granulocytic and nongranulocytic BBS cells. However, NF-κB activity highly correlated to granulocyte percentage and was only abrogated after granulocytic death in cultured BBSs. Before granulocytic death, NF-κB activity was suppressed by simultaneous addition of neutralizing anti-IL-1β and anti-TNF-α Abs to the medium of cultured BBSs. Surprisingly, IκB-β, whose expression is not regulated by NF-κB, unlike IκB-α, was the most prominent NF-κB inhibitor found in BBSs. The amounts of IκB-β were low in BBSs obtained from diseased horses, but drastically increased after addition of the neutralizing anti-IL-1β and anti-TNF-α Abs. These results indicate that sustained NF-κB activation in asthmatic bronchi is driven by granulocytes and is mediated by IL-1β and TNF-α. Moreover, an imbalance between high levels of IL-1β- and TNF-α-mediated IκB-β degradation and low levels of IκB-β synthesis is likely to be the mechanism preventing NF-κB deactivation in asthmatic airways before granulocytic death.

Asthma is a chronic inflammatory disease of the airways, in which many inflammatory genes are overexpressed. Transcription factor, nuclear factor- κ B (NF- κ B), which is thought to control the transcriptional initiation of inflammatory genes, has been poorly investigated in asthma. In the present report, bronchial cells (BCs), recovered by bronchial brushing in healthy and heaves-affected horses (i.e., an animal model of asthma), were assessed for NF- κ B activity. Small amounts of active NF- κ B were present in BCs of healthy horses, whereas high levels of NF- κ B activity was found during crisis (i.e., acute airway obstruction) in all heaves-affected horses. Three weeks after the crisis, the level of NF- κ B activity found in BCs of heaves-affected horses was highly correlated (p < 0.01) to the degree of residual lung dysfunction. Unexpectedly, active NF- κ B complexes found in BCs of heaves-affected horses were mainly p65 homodimers, rather than classic p65–p50 heterodimers. At last, intercellular adhesion molecule-1 (ICAM-1) expression paralleled p65 homodimers activity in these cells. These results demonstrate that the kinetics of NF- κ B activity is strongly related to the course of the disease and confirm the relevance of NF- κ B as a putative target in asthma therapy. Moreover, uncommon p65 homodimers could transactivate, in BCs, a subset of genes, such as ICAM-1, characteristic of chronic airway inflammation.