NF-kappaB, Nrf2, and HO-1 interplay in redox-regulated VCAM-1 expression

Antioxid Redox Signal. Jul-Aug 2005;7(7-8):889-99. doi: 10.1089/ars.2005.7.889.

Abstract

Oxidative processes are considered to play a crucial role in the induction of cell adhesion molecules, a key event in inflammatory processes. We recently reported on an unexpected unidirectional effect of an overexpressed antioxidant [phospholipid hydroperoxide glutathione peroxidase (PHGPx)] and an oxidant [15-lipoxygenase (15-LOX)] enzyme on the basal and interleukin-1 induced vascular cell adhesion molecule-1 (VCAM-1) expression in vascular smooth muscle cells (SMC). Both enzymes inhibited VCAM-1 expression and reduced the cellular protein thiol content, thus, both exerting an oxidant effect. We now investigated whether transcription factors known to be regulated by oxidation, i.e., the nuclear factor-kappaB and the Keap1/Nrf2 system, were affected in our set of cells: SMC, SMC(PHGPx), and SMC(LOX), as well as ECV and ECV(PHGPx). PHGPx and 15-LOX inhibited nuclear factor-kappaB activation most efficiently at a step downstream of DNA binding, which explains their inhibitory effect on VCAM-1 expression. Both enzymes up-regulated endogenous heme oxygenase-1 most probably via activation of Nrf2. Transfected Nrf2 strongly inhibited VCAM-1 promoter activity, which could be reversed by cotransfection with Keap1. The key player in this complex cross-talk obviously is heme oxygenase-1, which is known to be induced by oxidant-activated Nrf2. The moderate oxidative stress initiated by enhanced PHGPx or 15-LOX activity appears to induce a defense system that diminishes the response to further proinflammatory stimuli.

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Animals
  • Arachidonate 15-Lipoxygenase / genetics
  • Arachidonate 15-Lipoxygenase / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation* / drug effects
  • Glutathione Peroxidase / genetics
  • Glutathione Peroxidase / metabolism
  • Heme Oxygenase (Decyclizing) / metabolism*
  • Heme Oxygenase-1
  • Interleukin-1 / pharmacology
  • Mutation / genetics
  • NF-E2-Related Factor 2
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Oxidation-Reduction
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Phosphorylation
  • Promoter Regions, Genetic / genetics
  • Protein Subunits / metabolism
  • Rabbits
  • Trans-Activators / metabolism*
  • Transcriptional Activation / genetics
  • Vascular Cell Adhesion Molecule-1 / genetics
  • Vascular Cell Adhesion Molecule-1 / metabolism*

Substances

  • DNA-Binding Proteins
  • Interleukin-1
  • NF-E2-Related Factor 2
  • NF-kappa B
  • Protein Subunits
  • Trans-Activators
  • Vascular Cell Adhesion Molecule-1
  • DNA
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Glutathione Peroxidase
  • Arachidonate 15-Lipoxygenase
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1