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Am. J. Respir. Cell Mol. Biol., Volume 24, Number 6, June, 2001 769-777

Hydrogen Peroxide Has Opposing Effects on IKK Activity and Ikappa Balpha Breakdown in Airway Epithelial Cells

Ilona Jaspers, Wenli Zhang, Alison Fraser, James M. Samet, and William Reed

Center for Environmental Medicine and Lung Biology, University of North Carolina School of Medicine, Chapel Hill; and Human Studies Division, National Health and Environmental Effects Research Laboratory, Environmental Protection Agency, Research Triangle Park, North Carolina

Recent studies have advanced our knowledge about the signal transduction cascade involved in the activation of nuclear factor (NF) kappa B, including the identification and characterization of Ikappa B kinases (IKKs). Although exposure to hydrogen peroxide (H2O2) in vitro can activate NF-kappa B, this response is not universal and depends on the cell type and transformation state. In this study, we examined the effects of H2O2 on IKKs and activation of NF-kappa B in primary normal human bronchial epithelial (NHBE) cells. Our results demonstrate that treatment with H2O2 increased IKK activity, phosphorylation, and ubiquitination of Ikappa Balpha in NHBE cells. However, there was no significant proteolytic degradation of Ikappa Balpha , nuclear translocation of p65, or NF-kappa B DNA binding activity in cells treated with H2O2. Treatment with H2O2 also inhibited tumor necrosis factor (TNF)-alpha -induced Ikappa Balpha breakdown, NF-kappa B DNA binding activity, and NF-kappa B-dependent transcription but had no effect on TNF-alpha -induced Ikappa Balpha phosphorylation or ubiquitination. Furthermore, treatment with H2O2 alone or in combination with TNF-alpha increased the levels of other ubiquitinated proteins in NHBE cells, suggesting general inhibition of proteasomal activity by H2O2. Taken together, these results demonstrate that in airway epithelial cells treatment with H2O2 has opposing effects on IKK activity and proteasomal degradation of Ikappa Balpha , and suggest that H2O2 may suppress TNF-alpha -induced NF-kappa B- dependent gene expression.

Abbreviations: complementary DNA, cDNA; dithiothreitol, DTT; ethylenediaminetetraacetic acid, EDTA; glyceraldehyde-3-phosphate dehydrogenase, GAPDH; hydrogen peroxide H2O2; 4-hydroxy-2-nonenal, HNE; inhibitor of NF-kappa B, Ikappa B; Ikappa B kinase, IKK; interleukin, IL; mitogen-activated protein kinase, MAPK; MAPK kinase kinase, MAPKKK; major histocompatibility complex, MHC; messenger RNA, mRNA; nuclear factor kappa B, NF-kappa B; normal human bronchial epithelial cells, NHBE cell; rat lung epithelial cell, RLE cell; reactive oxygen intermediates, ROI; sodium dodecyl sulfate polyacrylamide gel electrophoresis, SDS-PAGE; tumor necrosis factor alpha, TNF-alpha .




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