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 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.
Zhang
J
J
Department of Pathology, University of Michigan, Ann Arbor 48109, USA.
Johnston
G
G
Stebler
B
B
Keller
E T
ET
D021581:Active Transport, Cell Nucleus; D000375:Aging; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D020672:I-kappa B Proteins; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics*; D007700:Kinetics; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology*; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D000097782:NF-kappaB-Inducing Kinase
D004268:DNA-Binding Proteins; D006861:Hydrogen Peroxide; D020672:I-kappa B Proteins; D015850:Interleukin-6; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D016877:Oxidants; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D000097782:NF-kappaB-Inducing Kinase; C000606204:NFKBIA protein, human