Gene-specific regulation of hepatic selenoprotein expression by interleukin-6

Metallomics. 2015 Nov;7(11):1515-21. doi: 10.1039/c5mt00211g. Epub 2015 Sep 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Glutathione Peroxidase / metabolism
  • Hep G2 Cells
  • Hepatocytes / metabolism
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Liver / metabolism*
  • Selenium / metabolism*
  • Selenoprotein P / genetics
  • Selenoprotein P / metabolism*
  • Sepsis


  • IL6 protein, human
  • Interleukin-6
  • Selenoprotein P
  • Glutathione Peroxidase
  • Selenium