Selenium supplementation has beneficial and detrimental effects on immunity to influenza vaccine in older adults.

BACKGROUND & AIMS: Mortality resulting from influenza (flu) virus infections occurs primarily in the elderly through declining immunity. Studies in mice have suggested beneficial effects of selenium (Se) supplementation on immunity to flu but similar evidence is lacking in humans. A dietary intervention study was therefore designed to test the effects of Se-supplementation on a variety of parameters of anti-flu immunity in healthy subjects aged 50-64 years. METHODS: A 12-week randomized, double-blinded, placebo-controlled clinical trial (ClinicalTrials.govNCT00279812) was undertaken in six groups of individuals with plasma Se levels <110 ng/mL. Four groups were given daily capsules of yeast enriched with 0 µg Se/day (SeY-0/d; n = 20), 50 µg Se/d (SeY-50/d; n = 18), 100 µg Se/d (SeY-100/d; n = 21) or 200 µg Se/d (SeY-200/d; n = 23). Two groups were given onion-containing meals with either <1 µg Se/d (SeO-0/d; n = 17) or 50 µg Se/d (SeO-50/d; n = 18). Flu vaccine was administrated at week 10 and immune parameters were assessed until week 12. RESULTS: Primary study endpoints were changes in cellular and humoral immune responses. Supplementation with SeY and SeO affected different aspects of cellular immunity. SeY increased Tctx-ADCC cell counts in blood (214%, SeY-100/d) before flu vaccination and a dose-dependent increase in T cell proliferation (500%, SeY-50/100/200/d), IL-8 (169%, SeY-100/d) and IL-10 (317%, SeY-200/d) secretion after in vivo flu challenge. Positive effects were contrasted by lower granzyme B content of CD8 cells (55%, SeY-200/d). SeO (Se 50 µg/d) also enhanced T cell proliferation after vaccination (650%), IFN-γ (289%), and IL-8 secretion (139%), granzyme (209%) and perforin (190%) content of CD8 cells but inhibited TNF-α synthesis (42%). Onion on its own reduced the number of NKT cells in blood (38%). These effects were determined by comparison to group-specific baseline yeast or onion control groups. Mucosal flu-specific antibody responses were unaffected by Se-supplementation. CONCLUSION: Se-supplementation in healthy human adults with marginal Se status resulted in both beneficial and detrimental effects on cellular immunity to flu that was affected by the form of Se, supplemental dose and delivery matrix. These observations call for a thorough evaluation of the risks and benefits associated with Se-supplementation.

Effects of selenium supplementation on selenoprotein gene expression and response to influenza vaccine challenge: a randomised controlled trial.

BACKGROUND: The uncertainty surrounding dietary requirements for selenium (Se) is partly due to limitations in biomarkers of Se status that are related to health outcomes. In this study we determined the effect of different doses and forms of Se on gene expression of selenoprotein S (SEPS1), selenoprotein W (SEPW1) and selenoprotein R (SEPR), and responses to an immune function challenge, influenza vaccine, were measured in order to identify functional markers of Se status. METHODS AND FINDINGS: A 12 week human dietary intervention study was undertaken in 119 volunteers who received placebo, 50, 100 or 200 µg/day Se-enriched yeast (Se-yeast) or meals containing unenriched or Se-enriched onions (50 µg/day). Gene expression was quantified in RNA samples extracted from human peripheral blood mononuclear cells (PBMC's) using quantitative RT-PCR. There was a significant increase in SEPW1 mRNA in the Se-enriched onion group (50 µg/day) compared with the unenriched onion group. SEPR and SEPW1 did not change significantly over the duration of the supplementation period in the control or Se-yeast groups, except at week 10 when SEPW1 mRNA levels were significantly lower in the 200 µg/day Se-yeast group compared to the placebo group. Levels of SEPS1 mRNA increased significantly 7 days after the influenza vaccine challenge, the magnitude of the increase in SEPS1 gene expression was dose-dependent, with a significantly greater response with higher Se supplementation. CONCLUSIONS: This novel finding provides preliminary evidence for a role of SEPS1 in the immune response, and further supports the relationship between Se status and immune function. TRIAL REGISTRATION: ClinicalTrials.gov [NCT00279812].

Establishing optimal selenium status: results of a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Dietary recommendations for selenium differ between countries, mainly because of uncertainties over the definition of optimal selenium status. OBJECTIVE: The objective was to examine the dose-response relations for different forms of selenium. DESIGN: A randomized, double-blind, placebo-controlled dietary intervention was carried out in 119 healthy men and women aged 50-64 y living in the United Kingdom. Daily placebo or selenium-enriched yeast tablets containing 50, 100, or 200 microg Se ( approximately 60% selenomethionine), selenium-enriched onion meals ( approximately 66% gamma-glutamyl-methylselenocysteine, providing the equivalent of 50 microg Se/d), or unenriched onion meals were consumed for 12 wk. Changes in platelet glutathione peroxidase activity and in plasma selenium and selenoprotein P concentrations were measured. RESULTS: The mean baseline plasma selenium concentration for all subjects was 95.7 +/- 11.5 ng/mL, which increased significantly by 10 wk to steady state concentrations of 118.3 +/- 13.1, 152.0 +/- 24.3, and 177.4 +/- 26.3 ng/mL in those who consumed 50, 100, or 200 microg Se-yeast/d, respectively. Platelet glutathione peroxidase activity did not change significantly in response to either dose or form of selenium. Selenoprotein P increased significantly in all selenium intervention groups from an overall baseline mean of 4.99 +/- 0.80 microg/mL to 6.17 +/- 0.85, 6.73 +/- 1.01, 6.59 +/- 0.64, and 5.72 +/- 0.75 microg/mL in those who consumed 50, 100, or 200 microg Se-yeast/d and 50 microg Se-enriched onions/d, respectively. CONCLUSIONS: Plasma selenoprotein P is a useful biomarker of status in populations with relatively low selenium intakes because it responds to different dietary forms of selenium. To optimize the plasma selenoprotein P concentration in this study, 50 microg Se/d was required in addition to the habitual intake of approximately 55 microg/d. In the context of established relations between plasma selenium and risk of cancer and mortality, and recognizing the important functions of selenoprotein P, these results provide important evidence for deriving estimated average requirements for selenium in adults. This trial was registered at clinicaltrials.gov as NCT00279812.

Se-methylselenocysteine alters collagen gene and protein expression in human prostate cells.

The anti-cancer activity of selenium is dose-dependent and species-specific but the mechanism is unclear. Se-methylselenocysteine (MSC), found in selenium-enriched alliums, is one of the most potent forms. We exposed two human prostate cell lines (LNCaP clone FGC and PNT1A) to nutritionally relevant doses of MSC and selenite, ranging from deficient to the equivalent of selenium supplementation in humans. The cells were adapted for one month to attain steady-state selenium status. Two microarray platforms, an in-house printed microarray (14,000 genes) and the Affymetrix U133A array (22,000 genes) were used to probe the molecular effects of selenium dose and form and several selenium-responsive genes were identified, many of which have been ascribed to cancer cell growth and progression. In response to MSC supplementation, the expression of 23 genes changed significantly, including several collagen genes. Quantitative RT-PCR assays were designed and optimized for four of the collagen genes to validate array data. Significant decreases in expression of collagen type I alpha 1 (COL1A1), COL1A2 and COL7A1 genes were observed in cells adapted to MSC supplementation compared to the control and selenite exposed cells. There were significant increases in genes encoding other types of collagen, including significant increases in COL6A1 and COL4A5 in response to MSC dose. Functional changes in collagen type I protein expression in response to MSC were confirmed by ELISA. This study reveals for the first time that MSC can alter the expression of several types of collagen and thus potentially modulate the extracellular matrix and stroma, which may at least partially explain the anti-cancer activity of MSC.