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

In most cells trans-activating NF-kappaB induces many inflammatory proteins as well as its own inhibitor, I kappaB-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-1 beta and anti-TNF-alpha Abs to the medium of cultured BBSs, Surprisingly, I kappaB-beta, whose expression is not regulated by NF-kappaB, unlike IKB-alpha, was the most prominent NF-kappaB inhibitor found in BBSs, The amounts of I kappaB-beta were low in BBSs obtained from diseased horses, but drastically increased after addition of the neutralizing anti-IL-1 beta 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-1 beta and TNF-alpha, Moreover, an imbalance between high levels of IL-1 beta- and TNF-alpha -mediated I kappaB-beta degradation and low levels of I kappaB-beta synthesis is likely to be the mechanism preventing NF-kappaB deactivation in asthmatic airways before granulocytic death.