NF-kappaB, Nrf2, and HO-1 interplay in redox-regulated VCAM-1 expression.
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.
German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany.
Antje
A
Banning
Regina
R
Brigelius-Flohé
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D007375:Interleukin-1 / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D021122:Protein Subunits / Q000378:metabolism; D011817:Rabbits; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D007375:Interleukin-1; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D021122:Protein Subunits; D015534:Trans-Activators; D019010:Vascular Cell Adhesion Molecule-1; D004247:DNA; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D001093:Arachidonate 15-Lipoxygenase; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1