Hydrogen peroxide activates NFkappaB and the interleukin-6 promoter through NFkappaB-inducing kinase

Aging is associated not only with oxidant stress, but also with increased interleukin-6 (IL-6) levels. To determine if oxidative stress could contribute to the age-associated increase IL-6 expression, we exposed LNCaP prostate carcinoma cells and HeLa cervical carcinoma cells to H2O2 as an oxidant c...

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Bibliographic Details
Published in:	Antioxidants & redox signaling Vol. 3; no. 3; p. 493
Main Authors:	Zhang, J, Johnston, G, Stebler, B, Keller, E T
Format:	Journal Article
Language:	English
Published:	United States 01-06-2001
Subjects:	Active Transport, Cell Nucleus Aging Cell Nucleus - metabolism DNA-Binding Proteins - physiology Dose-Response Relationship, Drug Female HeLa Cells Humans Hydrogen Peroxide - pharmacology I-kappa B Proteins Interleukin-6 - biosynthesis Interleukin-6 - genetics Kinetics Male NF-kappa B - metabolism NF-KappaB Inhibitor alpha NF-kappaB-Inducing Kinase Oxidants - pharmacology Oxidative Stress Promoter Regions, Genetic Protein Serine-Threonine Kinases - physiology RNA, Messenger - biosynthesis Transcriptional Activation Tumor Cells, Cultured
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Summary:	Aging is associated not only with oxidant stress, but also with increased interleukin-6 (IL-6) levels. To determine if oxidative stress could contribute to the age-associated increase IL-6 expression, we exposed LNCaP prostate carcinoma cells and HeLa cervical carcinoma cells to H2O2 as an oxidant challenge. We found that H2O2 induced IL-6 expression through activation of the IL-6 promoter. Furthermore, H2O2-induced activation of the promoter was mediated through nuclear factor-kappaB (NFkappaB) secondary to H2O2-induced phosphorylation and degradation of IkappaBalpha. NFkappaB-inducing kinase (NIK) is upstream of the IkappaB kinase complex that induces IkappaBalpha degradation. Accordingly, we explored if H2O2 induces IL-6 expression through NIK. In addition to H2O2 inducing NIK autophosphorylation, transfection of LNCaP cells with a dominant negative NIK diminished H2O2-mediated NFkappaB and IL-6 promoter activity. Taken together, these results demonstrate that H2O2 induces the IL-6 promoter by activating NFkappaB through NIK. These data provide a candidate mechanism through which oxidant challenge induces IL-6 gene expression with age.
ISSN:	1523-0864