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

Antioxid Redox Signal. 2001 Jun;3(3):493-504. doi: 10.1089/15230860152409121.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Oxidants / pharmacology*
  • Oxidative Stress
  • Promoter Regions, Genetic*
  • Protein-Serine-Threonine Kinases / physiology*
  • RNA, Messenger / biosynthesis
  • Transcriptional Activation
  • Tumor Cells, Cultured

Substances

  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Interleukin-6
  • NF-kappa B
  • NFKBIA protein, human
  • Oxidants
  • RNA, Messenger
  • NF-KappaB Inhibitor alpha
  • Hydrogen Peroxide
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase