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.
Highlights
The family of glutathione peroxidases (GPx) is crucial for the regulation of the intra- and extracellular redox balance by reducing hydroperoxides at the expense of glutathione [1]
We analyzed the mRNA expression of the pro-inflammatory mediator tumor necrosis factor (TNF)-α and of the enzymes inducible NO synthase (iNOS) and COX-2 in the intestine of wild type (WT) and Glutathione peroxidase 2 (GPx2) KO mice which were fed a seleniumadequate diet. mRNA levels of iNOS and TNF-α were upregulated in the intestine of GPx2 KO mice (Fig. 1A and B) while COX-2 only showed a trend
The levels of inhibitor of nuclear factor 'κlight-chain-enhancer’ of activated B-cells (NF-κB) (IκBα) were elevated in the intestinal epithelium of GPx2 KO mice (Fig. 1D), suggesting that IκBα is upregulated in a compensatory manner to reduce NF-κB activation in GPx2 KO animals
Summary
The family of glutathione peroxidases (GPx) is crucial for the regulation of the intra- and extracellular redox balance by reducing hydroperoxides at the expense of glutathione [1]. GPx4 is most important because its complete knockout (KO) is embryonically lethal for mice [2] while GPx1 or GPx2 KO mice only have very mild phenotypes [3,4] One reason for this strong dependency is the fact that GPx4 is the only isoform which has the ability to reduce complex hydroperoxides like phosphatidylcholine hydroperoxide [5]. For GPx1 and GPx2, no specific substrates have been identified so far, but both are able to reduce H2O2 and fatty acid-derived hydroperoxides. They clearly differ in their localization, e.g., along the crypt-villus axis of the intestinal epithelium. Whereas GPx2 ranks high in hierarchy and is expressed even under selenium restriction, GPx1 expression is highly dependent on the selenium supply indicating that GPx1 is more dispensable
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