Selenium controls the sex-specific immune response and selenoprotein expression during the acute-phase response in mice

Abstract

Selenium modifies inflammatory reactions in rodents and humans. The liver controls metabolism and transport of selenium via hepatically-derived SEPP (selenoprotein P). Intracellular SEPS (selenoprotein S) modifies endoplasmic-reticulum function and immune-cell activity. Polymorphisms in SEPS have been associated with cytokine levels and inflammatory diseases in a subset of clinical studies. In the present study, we hypothesized that sex and selenium represent decisive parameters controlling the immune response and regulation of SEPS expression in vivo. Male and female mice fed a selenium-poor diet were supplemented or not with selenite for 3 days and injected with saline or LPS (lipopolysaccharide) 24 h before analysis. Selenium supplementation mitigated the LPS-induced rise in circulating cytokines in male mice. Serum SepP and selenium concentrations decreased in response to LPS, whereas hepatic SepS was specifically up-regulated despite declining selenium concentrations in the liver. Hepatic SepS induction was mainly controlled by post-transcriptional mechanisms and attributed to hepatocytes by analysing transgenic mice. Notably, selenium supplementation was essential for an optimal SepS induction. We conclude that selenoprotein biosynthesis becomes redirected in hepatocytes during the acute-phase response at the expense of dispensable selenoproteins (e.g. SepP) and in favour of SepS expression, thereby causing declining serum selenium and improving liver function. The selenium status and sex control SepS expression and modify cytokine response patterns in serum, which might explain contradictory results on associations of SEPS genotype and inflammatory diseases in clinical studies.

The role of selenium in thyroid gland pathophysiology

“…Postuluje się wpływ żeńskich hormonów płciowych, ochronne działanie czynników zależnych od obecności chromosomu Y lub też odmienności w funkcjonowaniu układu immunologicznego u obu płci. Warto także podkreślić, że korzystny wpływ selenu na choroby tarczycy w więk-szości przypadków został wykazany u kobiet, podczas gdy u mężczyzn w wielu innych narządach [83,[95][96][97][98].…”

“…An influence of female sex hormones is postulated, as well as the protective activity of factors that depend on the presence of chromosome Y or on the different mechanisms by which the immune systems function in both sexes. It is also worth emphasising that the advantageous effects of selenium in cases of thyroid diseases have been demonstrated in women, while in men it has been shown in other organs [83,[95][96][97][98].…”

Transcriptomics and functional genetic polymorphisms as biomarkers of micronutrient function: focus on selenium as an exemplar

“…Reporter gene experiments indicate that the SNP have functional consequences. Second, SelS is another selenoprotein recently found to have a function in the ER stress response (33)(34)(35) . An SNP in the SELS promoter at position -105 is regarded as being functionally significant as it modulates levels of inflammatory markers such as TNF-a and interleukin (33) .…”

Chronic Kidney Disease Distinctly Affects Relationship Between Selenoprotein P Status and Serum Thyroid Hormone Parameters

“…This could be due to impaired Se and/ or SePP clearance with declining renal function, as SePP has been shown to be specifically bound by megalin in the healthy kidney of rodent models, likely preventing its loss or degradation (4,5). A significant negative correlation of SePP and CRP has also been reported, presumably due to altered hepatic SePP biosynthesis, as previously seen in cell culture studies and mouse models of acute phase response (28)(29)(30). However, in the present patients, the association of SePP with renal function was still present when corrected for CRP, highlighting the complexity of the interaction.…”