title: GPx2 Induction Is Mediated Through STAT Transcription Factors During Acute Colitis.
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.
authors.affiliation: Department of Molecular Toxicology, German Institute of Human Nutrition, Potsdam, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Hiller
authors.forename: Karolin
authors.initials: K
authors.lastname: Besselt
authors.forename: Stefanie
authors.initials: S
authors.lastname: Deubel
authors.forename: Regina
authors.initials: R
authors.lastname: Brigelius-Flohé
authors.forename: Anna P
authors.initials: AP
authors.lastname: Kipp
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D003106:Colon / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation; D000097043:Interleukin-22
chemical_list: D016207:Cytokines; D016264:Dextran Sulfate; D005979:Glutathione Peroxidase; D007155:Immunologic Factors; D007378:Interleukins; D019394:Ki-67 Antigen; D051267:NF-E2-Related Factor 2; D015230:Prostaglandin D2; D050791:STAT Transcription Factors; D000097043:Interleukin-22; C097240:15-deoxy-delta(12,14)-prostaglandin J2; C498355:Mki67 protein, mouse