Distinct and overlapping functions of glutathione peroxidases 1 and 2 in limiting NF-κB-driven inflammation through redox-active mechanisms

Redox Biol. 2020 Jan;28:101388. doi: 10.1016/j.redox.2019.101388. Epub 2019 Nov 16.

Abstract

Glutathione peroxidase 2 (GPx2) is one of the five selenoprotein GPxs having a selenocysteine in the active center. GPx2 is strongly expressed in the gastrointestinal epithelium, as is another isoform, GPx1, though with a different localization pattern. Both GPxs are redox-active enzymes that are important for the reduction of hydroperoxides. Studies on GPx2-deficient mice and human HT-29 cells with a stable knockdown (kd) of GPx2 revealed higher basal and IL-1β-induced expression of NF-κB target genes in vivo and in vitro. The activation of the IKK-IκBα-NF-κB pathway was increased in cultured GPx2 kd cells. Basal signaling was only restored by re-expressing active GPx2 in GPx2 kd cells but not by redox-inactive GPx2. As it is still not clear if the two isoforms GPx1 and GPx2 have different functions, kd cell lines for either GPx1 or GPx2 were studied in parallel. The inhibitory effect of GPx2 on NF-κB signaling and its target gene expression was stronger than that of GPx1, whereas cyclooxygenase (COX)- and lipoxygenase (LOX)-derived lipid mediator levels increased more strongly in GPx1 kd than in GPx2 kd cells. Under unstimulated conditions, the levels of the COX-derived prostaglandins PGE2 and PGD2 were enhanced in GPx2 as well as in GPx1 kd compared to control cells. Specifically, in GPx1 kd cells IL-1β stimulation led to a dramatic shift of the PGE2/PGD2 ratio towards pro-inflammatory PGE2. Taken together, GPx2 and GPx1 have overlapping functions in controlling inflammatory lipid mediator synthesis and, most probably, exert their anti-inflammatory effects by preventing excessive PGE2 production. In view of the high activity of COX and LOX pathways during inflammatory bowel disease our data therefore provide new insights into the mechanisms of the protective function of GPx1 and GPx2 during colitis as well as inflammation-driven carcinogenesis.

Keywords: Glutathione peroxidase; Inflammation; Inflammatory bowel disease; Lipid mediators; NF-κB; Prostaglandins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Regulation / drug effects
  • Gene Knockdown Techniques
  • Glutathione Peroxidase / genetics*
  • Glutathione Peroxidase / metabolism
  • HT29 Cells
  • Humans
  • Interleukin-1beta / genetics*
  • Lipoxygenase / genetics
  • Male
  • Mice
  • NF-kappa B / administration & dosage*
  • NF-kappa B / pharmacology
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Signal Transduction / drug effects
  • Up-Regulation

Substances

  • IL1B protein, human
  • Interleukin-1beta
  • NF-kappa B
  • GPX2 protein, human
  • glutathione peroxidase GPX1
  • Glutathione Peroxidase
  • Lipoxygenase
  • Prostaglandin-Endoperoxide Synthases