Hydrogen Peroxide Activates NF κ B and the Interleukin-6 Promoter Through NF κ B-Inducing Kinase

Abstract

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 IL6 expression through activation of the IL-6 promoter. Furthermore, H₂O₂-induced activation of the promoter was mediated through nuclear factor-κB (NFκB) secondary to H₂O₂-induced phosphorylation and degradation of IκBα. NFκB-inducing kinase (NIK) is upstream of the IκB kinase complex that induces IκBα 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 NFκB and IL-6 promoter activity. Taken together, these results demonstrate that H₂O₂ induces the IL-6 promoter by activating NFκB through NIK. These data provide a candidate mechanism through which oxidant challenge induces IL-6 gene expression with age.