Short-term modulation of interleukin-1beta signaling by hyperoxia: uncoupling of IkappaB kinase activation and NF-kappaB-dependent gene expression.

Abstract

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.

• Authors: Kelli Odoms, Thomas P Shanley, Hector R Wong
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 286 Issue 3 Pg. L554-62 (Mar 2004) ISSN: 1040-0605 [Print] United States
• PMID: 14617515 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• I-kappa B Proteins
• Interleukin-1
• Interleukin-8
• NF-kappa B
• NFKBIA protein, human
• Transcription Factor RelA
• NF-KappaB Inhibitor alpha
• Protein Kinases
• Interleukin-1 Receptor-Associated Kinases
• Protein Serine-Threonine Kinases
• CHUK protein, human
• I-kappa B Kinase
• IKBKB protein, human
• IKBKE protein, human

Topics

• Cell Line
• Epithelial Cells (cytology, metabolism)
• Gene Expression (immunology)
• Humans
• Hyperoxia (immunology, metabolism)
• I-kappa B Kinase
• I-kappa B Proteins (metabolism)
• Interleukin-1 (metabolism)
• Interleukin-1 Receptor-Associated Kinases
• Interleukin-8 (genetics)
• NF-KappaB Inhibitor alpha
• NF-kappa B (genetics, metabolism)
• Oxidative Stress (immunology)
• Phosphorylation
• Pneumonia (immunology, metabolism)
• Promoter Regions, Genetic
• Protein Kinases (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Respiratory Mucosa (cytology)
• Signal Transduction (immunology)
• Transcription Factor RelA