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  • Title: GPx2 Induction Is Mediated Through STAT Transcription Factors During Acute Colitis.
    Author: Hiller F, Besselt K, Deubel S, Brigelius-Flohé R, Kipp AP.
    Journal: Inflamm Bowel Dis; 2015 Sep; 21(9):2078-89. PubMed ID: 26115075.
    Abstract:
    BACKGROUND: The selenoprotein glutathione peroxidase 2 (GPx2) is highly expressed in the gastrointestinal epithelium. During inflammatory bowel disease and colorectal cancer, GPx2 expression is enhanced. METHODS: We analyzed GPx2 expression and transcriptional regulation during the different phases of dextran sulfate sodium (DSS)-induced colitis in mice and in cytokine-treated colorectal cancer cells. RESULTS: In the colon of DSS-treated mice, GPx2 was upregulated during the acute and recovery phase. In the latter, it was specifically localized in regenerating ki67-positive crypts next to ulcerations. In cultured cells, endogenous GPx2 expression and GPx2 promoter activity were enhanced by the anti-inflammatory mediators 15-deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) and interleukin-22 (IL-22), while it was unaffected by classical proinflammatory cytokines like IL-1β. Induction of GPx2 expression by 15d-PGJ2 was mediated through Nrf2. In contrast, in DSS-treated Nrf2-KO mice GPx2 expression remained upregulated during recovery, which appeared to be independent of Nrf2. IL-22 activates transcription factors of the signal transducers and activators of transcription (STAT) family. Therefore, we analyzed the GPx2 promoter for putative STAT-responsive elements and identified 4 of them. Point mutation of the binding element next to the transcription start completely abolished promoter activation after IL-22 treatment and after cotransfection of STAT expression plasmids. To show in vivo relevance of the obtained results, we performed immunohistochemistry for phospho-STAT3 and GPx2. Especially during acute colitis, GPx2 and nuclear STAT3 colocalized in inflamed areas. CONCLUSIONS: GPx2 is a novel target of STAT transcription factors. The upregulation of GPx2 by IL-22 indicates that GPx2 might be important for the resolution of inflammation.
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