We have been interested in elucidating how simultaneous stimuli modulate
inflammation-related signal transduction pathways in lung parenchymal cells. We previously demonstrated that exposing respiratory epithelial cells to 95%
oxygen (
hyperoxia) synergistically increased
tumor necrosis factor-alpha (
TNF-alpha)-mediated activation of
NF-kappaB and
NF-kappaB-dependent gene expression by a mechanism involving increased activation of
IkappaB kinase (IKK). Because the signal transduction mechanisms induced by IL-1beta are distinct to that of
TNF-alpha, herein we sought to determine whether
hyperoxia modulates IL-1beta-dependent signal transduction. In A549 cells, simultaneous treatment with
hyperoxia and IL-1beta caused increased activation of IKK, prolonged the degradation of
IkappaBalpha, and prolonged the nuclear translocation and
DNA binding of
NF-kappaB compared with cells treated with IL-1beta alone in room air.
Hyperoxia did not affect IL-1beta-dependent degradation of the
interleukin receptor-associated
kinase differently from treatment with IL-beta alone. In contrast to the effects on the IKK/
IkappaBalpha/
NF-kappaB pathway, simultaneous treatment with
hyperoxia and IL-1beta did not augment
NF-kappaB-dependent gene expression compared with treatment with IL-1beta alone. Similar observations were made in a different human respiratory epithelial cell line, BEAS-2B cells. In addition, simultaneous treatment with
hyperoxia and IL-1beta caused hyperphosphorlyation of the
NF-kappaB p65 subunit compared with treatment with IL-1beta alone. In summary, concomitant treatment of A549 cells with
hyperoxia and IL-1beta augments activation of IKK, prolongs degradation of
IkappaBalpha, and prolongs nuclear translocation and
DNA binding of
NF-kappaB. This activation, however, is not coupled to increased expression of
NF-kappaB-dependent genes, and the mechanism of this decoupling is not related to decreased phosphorylation of p65.