In most cells trans-activating NF-kappaB induces many inflammatory proteins
as well as its own inhibitor, I kappaB-alpha, thus assuring a transient re
sponse upon stimulation. However, NF-kappaB-dependent inflammatory gene exp
ression is persistent in asthmatic bronchi, even after allergen eviction. I
n 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, N
F-kappaB activity highly correlated to granulocyte percentage and was only
abrogated after granulocytic death in cultured BBSs. Before granulocytic de
ath, NF-kappaB activity was suppressed by simultaneous addition of neutrali
zing 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 BBS
s, The amounts of I kappaB-beta were low in BBSs obtained from diseased hor
ses, but drastically increased after addition of the neutralizing anti-IL-1
beta and anti-TNF-alpha Abs, These results indicate that sustained NF-kapp
aB activation in asthmatic bronchi is driven by granulocytes and is mediate
d 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 level
s of I kappaB-beta synthesis is likely to be the mechanism preventing NF-ka
ppaB deactivation in asthmatic airways before granulocytic death.