title: Gene-specific regulation of hepatic selenoprotein expression by interleukin-6.
abstract: Sepsis is a severe inflammatory disease resulting in excessive production of pro-inflammatory cytokines including interleukin-6 (IL-6), causing oxidative stress, tissue damage and organ dysfunction. Health benefits have been observed upon selenium (Se) supplementation in severe sepsis. Selenium is incorporated into selenoproteins implicated in anti-oxidative defence, thyroid hormone metabolism and immunoregulation. Selenium metabolism is controlled by hepatocytes synthesizing and secreting the Se transporter selenoprotein P (SePP). The circulating SePP declines in sepsis causing low serum Se levels. Dysregulation of the hepatic selenoenzyme deiodinase type 1 (DIO1) potentially contributes to the low T3 (thyroid hormone) syndrome observed in severe diseases. We hypothesized that IL-6 affects hepatic selenoprotein biosynthesis directly. Testing human hepatocytes in culture, IL-6 reduced the concentrations of SePP mRNA and secreted SePP in a dose-dependent manner. In parallel, expression of DIO1 declined at the mRNA, protein and enzyme activity level. The effects of IL-6 on glutathione peroxidase (GPX) expression were isozyme-specific; GPX1 remained unaffected, while transcript concentrations of GPX2 increased and those of GPX4 decreased. This pattern of IL-6-dependent effects was mirrored in reporter gene experiments with SePP, DIO1, GPX1, and GPX2 promoter constructs pointing to direct transcriptional effects of IL-6. The redirection of hepatic selenoprotein biosynthesis by IL-6 may represent a central regulatory circuit responsible for the decline of serum Se and low T3 concentrations in sepsis. Accordingly, therapeutic IL-6 targeting may be effective for improving the Se and thyroid hormone status, adjuvant Se supplementation success and survival in sepsis.
authors.affiliation: Institut für Experimentelle Endokrinologie, Charité- Universitätsmedizin Berlin, CVK, Südring 10, D-13353 Berlin, Germany. lutz.schomburg@charite.de.
authors.forename: J
authors.initials: J
authors.lastname: Martitz
authors.forename: N-P
authors.initials: NP
authors.lastname: Becker
authors.forename: K
authors.initials: K
authors.lastname: Renko
authors.forename: M
authors.initials: M
authors.lastname: Stoedter
authors.forename: S
authors.initials: S
authors.lastname: Hybsier
authors.forename: L
authors.initials: L
authors.lastname: Schomburg
mesh_terms: D005979:Glutathione Peroxidase / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D012643:Selenium / Q000378:metabolism*; D051149:Selenoprotein P / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D051149:Selenoprotein P; D005979:Glutathione Peroxidase; D012643:Selenium