[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology Veterinary medicine & animal health
Author, co-author :
Bureau, Fabrice ; Université de Liège - ULiège > Département de sciences fonctionnelles > Physiologie
Delhalle, Sylvie; Université de Liège - ULiège > Département de sciences fonctionnelles > Physiologie
Bonizzi, Giuseppina; Université de Liège - ULiège > Laboratory of Medical Chemistry/Medical Oncology
Fievez, Laurence ; Université de Liège - ULiège > Département de sciences fonctionnelles > Physiologie
Dogne, Sophie; Université de Liège - ULiège > Département de sciences fonctionnelles > Physiologie
Kirschvink, Nathalie; Université de Liège - ULiège > Département de sciences fonctionnelles > Physiologie
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