Advertisement

Biological Trace Element Research

, Volume 155, Issue 2, pp 201–208 | Cite as

Dietary Selenium Supplementation and Whole Blood Gene Expression in Healthy North American Men

  • Wayne Chris HawkesEmail author
  • Diane Richter
  • Zeynep Alkan
Article

Abstract

Selenium (Se) is a trace nutrient required in microgram amounts, with a recommended dietary allowance of 55 μg/day in humans. The nutritional functions of Se are performed by a group of 25 selenoproteins containing the unusual amino acid selenocysteine at their active sites. The selenoproteins with known activities are oxidation–reduction enzymes with roles in antioxidant protection, redox homeostasis and signaling, and thyroid hormone metabolism. Both deficiencies and excesses of Se are associated with impaired innate and adaptive immune responses. We supplemented 16 healthy men for 1 year with 300 μg Se/day as high-Se yeast or placebo yeast and measured whole blood gene expression with DNA microarrays before and after supplementation. Protein phosphorylation was the main biological process in common among the Se-responsive genes, which included a prominent cluster of protein kinases, suggesting that protein phosphorylation in leukocytes is sensitive to Se supplementation. We found highly ranked clusters of genes associated with RNA processing and protein transport, suggesting that dietary Se may regulate protein expression in leukocytes at both the posttranscriptional and posttranslational levels. The main functional pathway affected by Se supplementation was FAS apoptosis signaling, and expression of genes associated with T cell and natural killer cell cytotoxicity was increased. At the same time, the numbers of circulating natural killer and T cells expressing activation markers decreased. These changes are consistent with an anti-inflammatory effect of Se supplementation exerted through regulation of protein phosphorylation.

Keywords

Selenium Supplementation Gene expression T lymphocyte Natural killer cell Microarray 

Notes

Acknowledgments

U.S. Department of Agriculture CRIS Project Nos. 5306-51530-009-00D and 5306-51530-018-00D supported this research. The authors gratefully acknowledge the excellent technical assistance of the Human Studies Unit of WHNRC and the clinical staff of the UC Davis Cowell Student Health Center for their assistance with the conduct of this study. The UC Davis Cancer Center Gene Expression Resource supported by NCI Cancer Center Support Grant P30 CA93373 performed the microarray labeling, hybridizations, and scanning. Mention of trade name, proprietary product, or specific equipment does not constitute a guarantee or warranty by the U.S. Department of Agriculture or the University of California, nor does it imply approval to the exclusion of other products that may be suitable. The opinions expressed herein represent those of the authors and do not necessarily represent those of the U.S. Department of Agriculture or the University of California. USDA is an equal opportunity provider and employer.

Supplementary material

12011_2013_9786_MOESM1_ESM.pdf (62 kb)
ESM 1 (PDF 62 kb)

References

  1. 1.
    Combs GF Jr, Combs SB (1986) The role of selenium in nutrition. Academic, San DiegoGoogle Scholar
  2. 2.
    Gladyshev VN, Stadtman TC, Hatfield DL, Jeang KT (1999) Levels of major selenoproteins in T cells decrease during HIV infection and low molecular mass selenium compounds increase. Proc Natl Acad Sci U S A 96:835–839PubMedCrossRefGoogle Scholar
  3. 3.
    Liu Q, Lauridsen E, Clausen J (1998) Different selenium-containing proteins in the extracellular and intracellular media of leucocytes cultivated in vitro. Biol Trace Elem Res 61:237–252PubMedCrossRefGoogle Scholar
  4. 4.
    Kakiuchi C, Ishiwata M, Nanko S, Ozaki N, Iwata N et al (2007) Up-regulation of ADM and SEPX1 in the lymphoblastoid cells of patients in monozygotic twins discordant for schizophrenia. Am J Med Genet B Neuropsychiatr Genet 14:14Google Scholar
  5. 5.
    Arthur JR, McKenzie RC, Beckett GJ (2003) Selenium in the immune system. J Nutr 133:1457S–1459SPubMedGoogle Scholar
  6. 6.
    Marsh JA, Combs GF Jr, Whitacre ME, Dietert RR (1986) Effect of selenium and vitamin E dietary deficiencies on chick lymphoid organ development. Proc Soc Exp Biol Med 182:425–436PubMedCrossRefGoogle Scholar
  7. 7.
    Ilback NG, Fohlman J, Friman G (1989) Protective effect of selenium on the development of coxsackievirus B3-induced inflammatory lesions in the murine myocardium. J Trace Elem Exp Med 2:257–266Google Scholar
  8. 8.
    Boyne R, Arthur JR, Wilson AB (1986) An in vivo and in vitro study of selenium deficiency and infection in rats. J Comp Pathol 96:379–386PubMedCrossRefGoogle Scholar
  9. 9.
    Boyne R, Arthur JR (1986) The response of selenium-deficient mice to Candida albicans infection. J Nutr 116:816–822PubMedGoogle Scholar
  10. 10.
    Reffett JK, Spears JW, Brown TT Jr (1988) Effect of dietary selenium and vitamin E on the primary and secondary immune response in lambs challenged with parainfluenza3 virus. J Anim Sci 66:1520–1528PubMedGoogle Scholar
  11. 11.
    Turner RJ, Wheatley LE, Beck NF (1985) Stimulatory effects of selenium on mitogen responses in lambs. Vet Immunol Immunopathol 8:119–124PubMedCrossRefGoogle Scholar
  12. 12.
    Aziz ES, Klesius PH, Frandsen JC (1984) Effects of selenium on polymorphonuclear leukocyte function in goats. Am J Vet Res 45:1715–1718PubMedGoogle Scholar
  13. 13.
    Broome CS, McArdle F, Kyle JA, Andrews F, Lowe NM et al (2004) An increase in selenium intake improves immune function and poliovirus handling in adults with marginal selenium status. Am J Clin Nutr 80:154–162PubMedGoogle Scholar
  14. 14.
    Peretz A, Neve J, Desmedt J, Duchateau J, Dramaix M et al (1991) Lymphocyte response is enhanced by supplementation of elderly subjects with selenium-enriched yeast. Am J Clin Nutr 53:1323–1328PubMedGoogle Scholar
  15. 15.
    Baum MK, Shor-Posner G, Lai S, Zhang G, Lai H et al (1997) High risk of HIV-related mortality is associated with selenium deficiency. J Acquir Immune Defic Syndr Hum Retrovirol 15:370–374PubMedCrossRefGoogle Scholar
  16. 16.
    Campa A, Shor-Posner G, Indacochea F, Zhang GY, Lai H et al (1999) Mortality risk in selenium-deficient HIV-positive children. J Acquir Immune Defic Syndr Hum Retrovirol 20:508–513PubMedCrossRefGoogle Scholar
  17. 17.
    Kupka R, Msamanga GI, Spiegelman D, Morris S, Mugusi F et al (2004) Selenium status is associated with accelerated HIV disease progression among HIV-1-infected pregnant women in Tanzania. J Nutr 134:2556–2560PubMedGoogle Scholar
  18. 18.
    Huang Z, Rose AH, Hoffmann PR (2012) The role of selenium in inflammation and immunity: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 16:705–743PubMedCrossRefGoogle Scholar
  19. 19.
    Nair MPN, Schwartz SA (1990) Immunoregulation of natural and lymphokine-activated killer cells by selenium. Immunopharmacology 19:177–184PubMedCrossRefGoogle Scholar
  20. 20.
    Peng X, Cui H, Cui Y, Deng J, Zuo Z et al (2011) Lesions of thymus and decreased percentages of the peripheral blood T-cell subsets in chickens fed on diets excess in selenium. Hum Exp Toxicol 30:1972–1978PubMedCrossRefGoogle Scholar
  21. 21.
    Hardy G, Hardy I, Manzanares W (2012) Selenium supplementation in the critically ill. Nutr Clin Pract 27:21–33PubMedCrossRefGoogle Scholar
  22. 22.
    Jin C, Henao-Mejia J, Flavell RA (2013) Innate immune receptors: key regulators of metabolic disease progression. Cell Metab 17:873–882PubMedCrossRefGoogle Scholar
  23. 23.
    Panel on Dietary Antioxidants and Related Compounds, Subcommittee on Upper Reference Levels of Nutrients, Subcommittee on Interpretation and Uses of DRIs, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board (2000) Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. National Academy Press, Washington, DC, 529 ppGoogle Scholar
  24. 24.
    Laclaustra M, Navas-Acien A, Stranges S, Ordovas JM, Guallar E (2009) Serum selenium concentrations and diabetes in U.S. adults: National Health and Nutrition Examination Survey (NHANES) 2003–2004. Environ Heal Perspect 117:1409–1413Google Scholar
  25. 25.
    Stranges S, Marshall JR, Natarajan R, Donahue RP, Trevisan M et al (2007) Effects of long-term selenium supplementation on the incidence of type 2 diabetes: a randomized trial. Ann Intern Med 147:217–223PubMedCrossRefGoogle Scholar
  26. 26.
    Park K, Rimm EB, Siscovick DS, Spiegelman D, Manson JE et al (2012) Toenail selenium and incidence of type 2 diabetes in U.S. men and women. Diabetes Care 35:1544–1551PubMedCrossRefGoogle Scholar
  27. 27.
    McClung JP, Roneker CA, Mu W, Lisk DJ, Langlais P et al (2004) Development of insulin resistance and obesity in mice overexpressing cellular glutathione peroxidase. Proc Natl Acad Sci U S A 101:8852–8857PubMedCrossRefGoogle Scholar
  28. 28.
    Loh K, Deng H, Fukushima A, Cai X, Boivin B et al (2009) Reactive oxygen species enhance insulin sensitivity. Cell Metab 10:260–272PubMedCrossRefGoogle Scholar
  29. 29.
    Hawkes WC, Keim NL, Richter BD, Gustafson MB, Gale B et al (2008) High-selenium yeast supplementation in free-living North American men: no effect on thyroid hormone metabolism or body composition. J Trace Elem Med Biol 22:131–142PubMedCrossRefGoogle Scholar
  30. 30.
    Hawkes WC, Richter BD, Alkan Z, Souza EC, Derricote M et al (2008) Response of selenium status indicators to supplementation of healthy North American men with high-selenium yeast. Biol Trace Elem Res 122:107–121PubMedCrossRefGoogle Scholar
  31. 31.
    Affymetrix (2004) Affymetrix GeneChip expression analysis technical manual. Affymetrix, Santa ClaraGoogle Scholar
  32. 32.
    Liu WM, Mei R, Di X, Ryder TB, Hubbell E et al (2002) Analysis of high density expression microarrays with signed-rank call algorithms. Bioinformatics 18:1593–1599PubMedCrossRefGoogle Scholar
  33. 33.
    Hawkes WC, Hwang A, Alkan Z (2009) The effect of selenium supplementation on DTH skin responses in healthy North American men. J Trace Elem Med Biol 23:272–280PubMedCrossRefGoogle Scholar
  34. 34.
    Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W et al (2003) DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 4:P3PubMedCrossRefGoogle Scholar
  35. 35.
    Goldson AJ, Fairweather-Tait SJ, Armah CN, Bao Y, Broadley MR et al (2011) Effects of selenium supplementation on selenoprotein gene expression and response to influenza vaccine challenge: a randomised controlled trial. PLoS One 6:e14771PubMedCrossRefGoogle Scholar
  36. 36.
    Hawkes WC, Alkan Z (2012) Delayed cell cycle progression in selenoprotein W depleted cells is regulated by a mitogen-activated protein kinase kinase 4 (MKK4)-p38/c-Jun NH2-terminal kinase (JNK)-p53 pathway. J Biol Chem 287:27371–27379PubMedCrossRefGoogle Scholar
  37. 37.
    Hawkes WC, Wang TTY, Alkan Z, Richter BD, Dawson K (2009) Selenoprotein W modulates control of cell cycle entry. Biol Trace Elem Res 131:229–244PubMedCrossRefGoogle Scholar
  38. 38.
    Pardo J, Aguilo JI, Anel A, Martin P, Joeckel L et al (2009) The biology of cytotoxic cell granule exocytosis pathway: granzymes have evolved to induce cell death and inflammation. Microbes Infect 11:452–459PubMedCrossRefGoogle Scholar
  39. 39.
    Eitzen G, Lo AN, Mitchell T, Kim JD, Chao DV et al (2011) Proteomic analysis of secretagogue-stimulated neutrophils implicates a role for actin and actin-interacting proteins in Rac2-mediated granule exocytosis. Proc Natl Acad Sci U S A 9:70Google Scholar
  40. 40.
    Kikuchi-Maki A, Catina TL, Campbell KS (2005) Cutting edge: KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. J Immunol 174:3859–3863PubMedGoogle Scholar
  41. 41.
    Dong C, Davis RJ, Flavell RA (2002) MAP kinases in the immune response. Annu Rev Immunol 20:55–72PubMedCrossRefGoogle Scholar
  42. 42.
    Schieven GL (2009) The p38alpha kinase plays a central role in inflammation. Curr Top Med Chem 9:1038–1048PubMedCrossRefGoogle Scholar
  43. 43.
    Tietzel I, Mosser DM (2002) The modulation of macrophage activation by tyrosine phosphorylation. Front Biosci 7:d1494–d1502PubMedCrossRefGoogle Scholar
  44. 44.
    Raskovalova T, Lokshin A, Huang X, Jackson EK, Gorelik E (2006) Adenosine-mediated inhibition of cytotoxic activity and cytokine production by IL-2/NKp46-activated NK cells: involvement of protein kinase A isozyme I (PKA I). Immunol Res 36:91–99PubMedCrossRefGoogle Scholar
  45. 45.
    Rajani DK, Walch M, Martinvalet D, Thomas MP, Lieberman J (2012) Alterations in RNA processing during immune-mediated programmed cell death. Proc Natl Acad Sci U S A 109:8688–8693PubMedCrossRefGoogle Scholar
  46. 46.
    Zhou L, Park JJ, Zheng Q, Dong Z, Mi Q (2011) MicroRNAs are key regulators controlling iNKT and regulatory T-cell development and function. Cell Mol Immunol 8:380–387PubMedCrossRefGoogle Scholar
  47. 47.
    Bashan N, Kovsan J, Kachko I, Ovadia H, Rudich A (2009) Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen species. Physiol Rev 89:27–71PubMedCrossRefGoogle Scholar
  48. 48.
    Mesquita FS, Dyer SN, Heinrich DA, Bulun SE, Marsh EE et al (2010) Reactive oxygen species mediate mitogenic growth factor signaling pathways in human leiomyoma smooth muscle cells. Biol Reprod 82:341–351PubMedCrossRefGoogle Scholar
  49. 49.
    Pfeifer H, Conrad M, Roethlein D, Kyriakopoulos A, Brielmeier M et al (2001) Identification of a specific sperm nuclei selenoenzyme necessary for protamine thiol cross-linking during sperm maturation. Faseb J 15:1236–1238PubMedCrossRefGoogle Scholar
  50. 50.
    Corcoran A, Cotter TG (2013) Redox regulation of protein kinases. Febs J 280:1944–1965PubMedCrossRefGoogle Scholar
  51. 51.
    Dalle-Donne I, Rossi R, Giustarini D, Colombo R, Milzani A (2007) S-Glutathionylation in protein redox regulation. Free Radic Biol Med 43:883–898PubMedCrossRefGoogle Scholar
  52. 52.
    Stapleton SR, Garlock GL, Foellmi-Adams L, Kletzien RF (1997) Selenium: potent stimulator of tyrosyl phosphorylation and activator of MAP kinase. Biochim Biophys Acta 1355:259–269PubMedCrossRefGoogle Scholar
  53. 53.
    Lenart A, Pawlowski K (2013) Intersection of selenoproteins and kinase signalling. Biochim Biophys Acta 1834:1279–1284PubMedCrossRefGoogle Scholar
  54. 54.
    Sun QA, Wu YL, Zappacosta F, Jeang KT, Lee BJ et al (1999) Redox regulation of cell signaling by selenocysteine in mammalian thioredoxin reductases. J Biol Chem 274:24522–24530PubMedCrossRefGoogle Scholar
  55. 55.
    Larsen PR (1997) Update on the human iodothyronine selenodeiodinases, the enzymes regulating the activation and inactivation of thyroid hormone. Biochem Soc Trans 25:588–592PubMedGoogle Scholar
  56. 56.
    Yeh JY, Ou BR, Forsberg NE, Whanger PD (1997) Effects of selenium and serum on selenoprotein W in cultured L8 muscle cells. Biometals 10:11–22PubMedCrossRefGoogle Scholar
  57. 57.
    Hawkes WC, Kelley DS, Taylor PC (2001) The effects of dietary selenium on the immune system in healthy men. Biol Trace Elem Res 81:189–213PubMedCrossRefGoogle Scholar
  58. 58.
    Pagmantidis V, Meplan C, van Schothorst EM, Keijer J, Hesketh JE (2008) Supplementation of healthy volunteers with nutritionally relevant amounts of selenium increases the expression of lymphocyte protein biosynthesis genes. Am J Clin Nutr 87:181–189PubMedGoogle Scholar
  59. 59.
    Hooven LA, Butler J, Ream LW, Whanger PD (2006) Microarray analysis of selenium-depleted and selenium-supplemented mice. Biol Trace Elem Res 109:173–179PubMedCrossRefGoogle Scholar
  60. 60.
    Kibriya MG, Jasmine F, Argos M, Verret WJ, Rakibuz-Zaman M et al (2007) Changes in gene expression profiles in response to selenium supplementation among individuals with arsenic-induced pre-malignant skin lesions. Toxicol Lett 169:162–176PubMedCrossRefGoogle Scholar
  61. 61.
    Roy M, Kiremidjianschumacher L, Wishe HI, Cohen MW, Stotzky G (1994) Supplementation with selenium and human immune cell functions. 1. Effect on lymphocyte proliferation and interleukin 2 receptor expression. Biol Trace Elem Res 41:103–114PubMedCrossRefGoogle Scholar
  62. 62.
    Kiremidjian-Schumacher L, Roy M, Wishe HI, Cohen MW, Stotzky G (1994) Supplementation with selenium and human immune cell functions. 2. Effect on cytotoxic lymphocytes and natural killer cells. Biol Trace Elem Res 41:115–127PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York (outside the USA) 2013

Authors and Affiliations

  • Wayne Chris Hawkes
    • 1
    Email author
  • Diane Richter
    • 2
  • Zeynep Alkan
    • 1
  1. 1.United States Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research CenterUniversity of California DavisDavisUSA
  2. 2.Department of NutritionUniversity of California DavisDavisUSA

Personalised recommendations