Selenium and Inflammation: Underlying Anti-inflammatory Mechanisms

Abstract

The essential trace element selenium (Se), in the form of selenoproteins, plays a pivotal role in the antioxidant defense system of the cell. There is evidence that Se may confer benefits in patients with inflammatory disease and even infectious diseases like HIV. Furthermore, in patients with severe sepsis, characterized by an increase in reactive oxygen species and low endogenous anti-oxidative capacity, as well as in patients with systemic inflammatory response syndrome, Se supplementation may reduce mortality and improve the clinical outcome, respectively. The nuclear factor kappa-B (NF-κB) signaling pathway has been associated with enhanced inflammatory response and its activation has been significantly correlated with interleukin-6 and TNF-α production. Selenium may inhibit the activation of NF-κB by modulating selenoprotein genes expression. Moreover, Se supplementation in chronic inflammation restores the depleted hepatic and serum Se levels by increasing selenoprotein biosynthesis leading to suppressed CRP production thereby attenuating the inflammatory process. Se increases shedding of L-selectin from monocytes while decreasing soluble L-selectin, which has been reported to be associated with high mortality in patients with sepsis. These mechanisms are likely to contribute to the modulatory effects of an increased Se status on the inflammatory response. This review evaluates some apparently key mechanisms of the anti-inflammatory action of selenium and advocates Se supplementation as a modulator of inflammatory response in infectious and autoimmune disease. Prospective, randomized, controlled studies must be performed to provide a greater degree of certainty.

Key words

selenium - inflammation - selenoproteins - NF-κB - CRP

References

• 1 Köhrle J, Jakob F, Contempre B, Dumont JE. Selenium, the thyroid, and the endocrine system.  Endocr Rev. 2005;  26 944-984
• 2 Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG. Selenium: biochemical role as a component of glutathione peroxidase.  Sci Mag. 1973;  179 558-590
• 3 Berry MJ, Banu L, Larsen PR. Type I iodothyronine deiodinase is a selenocysteine-containing enzyme.  Nature. 1991;  349 438-440
• 4 Köhrle J. The deiodinase family: Selenoenzymes regulating thy-roid hormone availability and action.  Cell Mol Life Sci. 2000;  57 1853-1863
• 5 Gaertner R, Gasnier BC. Selenium in the treatment of autoimmune thyroiditis.  Biofactors. 2003;  19 165-170
• 6 Duntas LH, Mantzou E, Koutras DA. Effects of a six month treatment with selenomethionine in patients with autoimmune thyroiditis.  Eur J Endocrinol. 2003;  148 389-393
• 7 Turker O, Kumanlioglu K, Karapolat I, Dogan I. Selenium treatment in autoimmune thyroiditis: 9-month follow-up with variable doses.  J Endocrinol. 2006;  190 151-156
• 8 Mazokopakis EE, Papadakis JA, Papadomanolaki MG, Batistakis AG, Giannakopoulos TG, Protopapadakis EE, Ganotakis ES. Effects of 12 months treatment with L-selenomethionine on serum anti-TPO Levels in patients with Hashimoto's thyroiditis.  Thyroid. 2007;  17 609-612
• 9 Negro R, Greco G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H. The influence of selenium supplementation on postpartum thyroid status in pregnant women with thyroid peroxidase autoantibodies.  J Clin Endocrinol Metab. 2007;  92 1263-1268
• 10 Duntas LH. The role of selenium in thyroid autoimmunity and cancer.  Thyroid. 2006;  16 455-460
• 11 Moncayo R, Moncayo H. Nutritional treatment of incipient thyroid autoimmune disease. Influence of selenium supplementation on thyroid function and morphology in children and young adults.  Clin Nutr. 2005;  24 530-531
• 12 Thomson CD, MacLachlan SK, Grant AM, Paterson E, Lillico AJ. The effect of selenium on thyroid status in a population with marginal selenium and iodine status.  Br J Nutr. 2005;  94 962-968
• 13 Ryan-Harshman M, Aldoori W. The relevance of selenium to immunity, cancer, and infectious/inflammatory diseases.  Can J Diet Pract Res. 2005;  66 98-102
• 14 Esch T, Stefano GB. Proinflammation: a common denominator or initiator of different pathophysiological disease processes.  Med Sci Monit. 2002;  8 1-9
• 15 Esch T, Stefano GB, Fricchione GL, Benson H. Stress in cardiovascular diseases.  Med Sci Monit. 2002;  8 93-101
• 16 Elenkov IJ, Iezzoni DG, Daly A, Harris AG, Chrousos GP. Cytokine dysregulation, inflammation and well-being.  Neuroimmunomodulation. 2005;  12 255-269
• 17 Kopp EB, Ghosh S. NF-κB and rel proteins in innate immunity.  Adv Immunol. 1995;  58 1-27
• 18 Barnes PJ, Karin M. Nuclear Factor-B – a pivotal transcription factor in chronic inflammatory diseases.  New Engl J Med. 1997;  336 1066-1071
• 19 Albelda SM, Smith CW, Ward PA. Adhesion molecules and inflammatory injury.  FASEB J. 1994;  8 504-512
• 20 Zhu Z, Tang W, Ray A, Wu Y, Einarsson O, Landry ML, Gwaltney Jr J, Elias JA. Rhinovirous stimulation of interleukin-6 in vivo and in vitro: evidence for nuclear factor κB-dependent transcriptional activation.  J Clin Invest. 1996;  97 421-430
• 21 Cilberto G, Acrone R, Wagner EF, Ruther U. Inducible and tissue-specific expression of human C-reactive protein in transgenic mice.  EMBO J. 1987;  6 4017-4022
• 22 Maehira F, Luyo GA, Miyagi I, Oshiro M, Yamaneb N, Kuba M, Nakazato Y. Alterations of serum selenium concentrations in the acute phase of pathological conditions.  Clin Chim Acta. 2002;  316 137-146
• 23 Galley HF, Davies MJ, Webster NR. Xantine oxidase activity and free radical generation in patients with sepsis syndrome.  Crit Care Med. 1996;  24 1649-1653
• 24 Sakr Y, Reinhart K, Bloos F, Marx G, Russwurm S, Bauer M, Brunkhorst F. Time course and relationship between plasma selenium concentrations, systemic inflammatory response, sepsis, and multiorgan failure.  Br J Anaesth. 2007;  98 775-784
• 25 Angstwurm MW, Shottdorf J, Schopohl J, Gaertner R. Selenium replacement in patients with severe systemic inflammatory response syndrome improves clinical outcome.  Crit Care Med. 1999;  27 1807-1813
• 26 Angstwurm MW, Engelman I, Zimmermann T, Lehmann C, Spes CH, Abel P, Strau R, Meier-Hellmann A, Insel R, Radke J, Schuttler J, Gartner R. Selenium in Intensive Care (SIC): Results of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock.  Crit Care Med. 2007;  35 118-126
• 27 Gartner R, Albrich W, Angstwurm MW. The effect of a selenium supplementation on the outcome of patients with severe systemic inflammation, burn and trauma.  Biofactors. 2001;  14 199-204
• 28 Forceville X, Laviolle B, Ananne D, Vitoux D, Bleichner G, Korach JM, Cantais E, Georges H, Soubirou JL, Combes A, Bellisant E. Effect of high doses of selenium, as sodium selenite, in septic shock: a placebo-controlled, randomized, double-blind, phase II study.  Crit Care. 2007;  11 R73
• 29 Molnar J, Garamvolgyi Z, Herold M, Adanyi N, Somogyi A, Rigo Jr J. Serum selenium concentrations correlate significantly with inflammatory biomarker high-sensitive CRP levels in Hungarian gestational diabetic and healthy pregnant women at mid-pregnancy.  Biol Trace Elem Res. 2008;  121 16-22
• 30 Scheurig AC, Thorand B, Fischer B, Heier M, Koenig W. Association between the intake of vitamins and trace elements from supplements and C-reactive protein: results of the MONICA/KORA Augsburg study.  Eur J Clin Nutr. 2008;  62 127-137
• 31 Di Sabatino A, Ciccocioppo R, Cupelli F, Cinque B, Millimaggi D, Clarkson MM, Paulli M, Cifone MG, Corazza GR. Epithelium derived interleukin 15 regulates intraepithelial lymphocyte Th1 cytokine production, cytotoxicity, and survival in celiac disease.  Gut. 2006;  55 469-477
• 32 Stazi AV, Trinti B. Selenium deficiency in celiac disease: risk of autoimmune thyroid diseases.  Minerva Med. 2008;  99 643-653
• 33 Kupka R, Msamanga GI, Spiegelman D, Rifai N, Hunter DJ, Fawzi WW. Selenium levels in relation to morbidity and mortality among children born to HIV-infected mothers.  Eur J Clin Nutr. 2005;  59 1250-1258
• 34 Kalantari P, Narayan V, Natarajan SK, Muralidhar K, Gandhi UH, Vunta H, Henderson AJ, Prabhu KS. Thioredoxin reductase – 1 negatively regulates HIV-1 transactivating protein Tat-dependent transcription in human macrophages.  J Biol Chem. 2008;  283 33183-33190
• 35 Foster HD. A role for the antioxidant defense system in preventing the transmission of HIV.  Med Hypotheses. 2007;  69 1277-1280
• 36 Irlam JH, Visser ME, Rollins N, Siegfried N. Micronutrient supplementation in children and adults with HIV infection.  Cochrane Database Syst Rev. 2005;  19 CD003650
• 37 Kupka R, Mugusi F, Aboud S, Msamanga GI, Finkelstein JL, Spiegelman D, Fawzi WW. Randomized, double-blind, placebo-controlled trial of selenium supplements among HIV-infected pregnant women in Tanzania: effects on maternal and child outcomes.  Am J Clin Nutr. 2008;  87 1802-1808
• 38 Villamor E, Mugusi F, Urassa W, Bosch RJ, Saathoff E, Matsumoto K, Meydani SN, Fawzi WW. A trial of the effect of micronutrient supplementation on treatment outcome, T cell counts, morbidity, and mortality in adults with pulmonary tuberculosis.  J Infect Dis. 2008;  197 1499-1505
• 39 Zamamiri-Davis F, Lu Y, Thompson JT, Prabhu KS, Reddy PV, Sordillo LM, Reddy CC. Nuclear factor-kappaB mediates over-expression of cyclooxygenase-2 during activation of RAW 264.7 macrophages in selenium deficiency.  Free Radic Biol Med. 2002;  32 890-897
• 40 Vunta H, Belda BJ, Arner RJ, Channa Reddy C, Vanden Heuvel JP, Sandeep Prabhu K. Selenium attenuates pro-inflammatory gene expression in macrophages.  Mol Nutr Food Res. 2008;  52 1316-1323
• 41 Zhang F, Yu W, Hargrove JL, Greenspan P, Dean RG, Taylor EW, Hartle DK. Inhibition of TNF-alpha induced ICAM-1, VCAM-1 and E-selectin expression by selenium.  Atherosclerosis. 2002;  161 381-386
• 42 Vunta H, Davis F, Palempalli UD, Bhat D, Arner RJ, Thompson JT, Peterson DG, Reddy CC, Phabhu KS. The anti-inflammatory effects of selenium are mediated through 15-deoxy-Delta12,14-prostaglandin J2 in macrophages.  J Biol Chem. 2007;  282 17964-17973
• 43 Kretz-Remy C, Arrigo AP. Selenium: a key element that controls NF-kappa B activation and I kappa B alpha half life.  Biofactors. 2001;  14 117-125
• 44 Maehira F, Miyagi I, Eguchi Y. Selenium regulates transcription factor NF-kappaB activation during the acute phase reaction.  Clin Chim Acta. 2003;  334 163-171
• 45 Ahrens I, Ellwanger C, Smith BK, Bassler N, Chen YC, Neudorfer I, Ludwig A, Bode C, Peter K. Selenium supplementation induces metalloproteinase-dependent L-selectin shedding from monocytes.  J Leukoc Biol. 2008;  83 1388-1395
• 46 Cao Y-Z, Reddy CC, Sordillo LM. Altered eicosanoid biosynthesis in selenium-deficient endothelial cells.  Free Radic Biol Med. 2000;  28 381-389
• 47 Yamamoto H, Endo T, Kiya T, Goto T, Sagae S, Ito E, Watanabe H, Kudo R. Activation of phospholipase D by prostaglandin F2 alpha in rat luteal cells and effects of inhibitors of arachidonic acid metabolism.  Postaglandins. 1995;  50 201-211
• 48 Cao Y-Z, Weaver JA, Reddy CC, Sordillo LM. Selenium deficiency alters the formation of eicosanoids and signal transduction in rat lymphocytes.  Prostaglandins Other Lipid Mediat. 2002;  70 131-143
• 49 Wang L, Fuster M, Sriramarao P, Esko JD. Endothelial heparin sulfate deficiency impairs L-selectin and chemokine-mediated neutrophil trafficking during inflammatory responses.  Nat Immunol. 2005;  6 902-910
• 50 Smalley DM, Ley K. L-selectin: mechanisms and physiological significance of ectodomain cleavage.  J Cell Mol Med. 2005;  9 255-266
• 51 Seidelin JB, Nielsen OH, Strom J. Soluble L-selectin levels predict survival in sepsis Intensive.  Care Med. 2001;  28 1613-1618
• 52 Hoffmann PR, Berry MJ. The influence of selenium on immune responses.  Mol Nutr Food Res. 2008;  52 1273-1280
• 53 Curran JE, Jowett JB, Elliott KS, Gao Y, Gluschenko K, Wang J, Abel Azim DM, Cai G, Mahaney MC, Comuzzie AG, Dyer TD, Walder KR, Zimmet P, MacCluer JW, Collier GR, Kissebah AH, Blangero J. Genetic variation in selenoprotein S influences inflammatory response.  Nat Genet. 2005;  37 1234-1241
• 54 Martinez A, Santiago JL, Varade J, Marquez A, Lamas JR, Mendoza JL, de la Calle H, Diaz-Rubio M, de la Concha EG, Fernandez-Gutierrez B, Urcelay E. Polymorphisms in the selenoprotein S gene: lack of association with autoimmune inflammatory diseases.  BMC Genomics. 2008;  9 329

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