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Short-term modulation of interleukin-1 signaling by hyperoxia: uncoupling of IB kinase activation and NF-B-dependent gene expression

Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Children's Hospital Research Foundation, Cincinnati, Ohio 45229

Submitted 16 June 2003 ; accepted in final form 12 November 2003

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- (TNF-)-mediated activation of NF-B and NF-B-dependent gene expression by a mechanism involving increased activation of IB kinase (IKK). Because the signal transduction mechanisms induced by IL-1 are distinct to that of TNF-, herein we sought to determine whether hyperoxia modulates IL-1-dependent signal transduction. In A549 cells, simultaneous treatment with hyperoxia and IL-1 caused increased activation of IKK, prolonged the degradation of IB, and prolonged the nuclear translocation and DNA binding of NF-B compared with cells treated with IL-1 alone in room air. Hyperoxia did not affect IL-1-dependent degradation of the interleukin receptor-associated kinase differently from treatment with IL- alone. In contrast to the effects on the IKK/IB/NF-B pathway, simultaneous treatment with hyperoxia and IL-1 did not augment NF-B-dependent gene expression compared with treatment with IL-1 alone. Similar observations were made in a different human respiratory epithelial cell line, BEAS-2B cells. In addition, simultaneous treatment with hyperoxia and IL-1 caused hyperphosphorlyation of the NF-B p65 subunit compared with treatment with IL-1 alone. In summary, concomitant treatment of A549 cells with hyperoxia and IL-1 augments activation of IKK, prolongs degradation of IB, and prolongs nuclear translocation and DNA binding of NF-B. This activation, however, is not coupled to increased expression of NF-B-dependent genes, and the mechanism of this decoupling is not related to decreased phosphorylation of p65.

cell signaling; oxidant stress; transcription factors; lung epithelium

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