Abstract
Zinc ions (Zn2+) are food components with favourable effects in infectious disease. Zn2+ is taken up into dendritic cells (DCs), key players in the regulation of innate and adaptive immunity. In other cell types, Zn2+ has been shown to stimulate the formation of ceramide, which is in turn known to trigger suicidal cell death. The present study explored whether Zn2+ modifies ceramide formation and survival of bone marrow derived DCs. To this end, DCs were isolated from acid sphingomyelinase knockout (asm −/−) and corresponding wild type (asm +/+) mice and treated with different concentrations of Zn2+. Ceramide formation was assessed with anti-ceramide antibodies in FACS and immunohistochemical analysis, sub-G1 cell population by FACS analysis, break down of phosphatidylserine asymmetry by annexin V binding, cell death by propidium iodide incorporation, metabolic cell activity by MTT assay, ROS production from dichlorofluorescein fluorescence and activation of MAPKs by Western blotting. The treatment of asm +/+ DCs with low Zn2+ concentrations (up to 100 μM) was followed by ceramide formation, increase in sub-G1 cell population and phosphatidylserine exposure, effects blunted in asm −/− DCs. The treatment of DCs with C2-ceramide increased the percentage of sub-G1 and apoptotic DCs from both genotypes. Zn2+ led to similar activation of MAPKs in asm +/+ and asm −/− DCs and did not affect ROS production. Higher concentrations of Zn2+ led to a marked increase of propidium iodide incorporation in DCs of both genotypes. The present study reveals that in DCs Zn2+ triggers ceramide formation, which in turn compromises cell survival.
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References
Murakami M, Hirano T (2008) Intracellular zinc homeostasis and zinc signaling. Cancer Sci 99:1515–1522
Prasad AS (1995) Zinc: an overview. Nutrition 11:93–99
Cuevas LE, Koyanagi A (2005) Zinc and infection: a review. Ann Trop Paediatr 25:149–160
Fischer-Walker C, Black RE (2004) Zinc and the risk for infectious disease. Annu Rev Nutr 24:255–275
Richard SA, Zavaleta N, Caulfield LE et al (2006) Zinc and iron supplementation and malaria, diarrhea, and respiratory infections in children in the Peruvian Amazon. Am J Trop Med Hyg 75:126–132
Hambidge KM (2006) Zinc and pneumonia. Am J Clin Nutr 83:991–992
Brown KH, Lopez dR, Arsenault JE et al (2007) Comparison of the effects of zinc delivered in a fortified food or a liquid supplement on the growth, morbidity, and plasma zinc concentrations of young Peruvian children. Am J Clin Nutr 85:538–547
Litonjua AA, Rifas-Shiman SL, Ly NP et al (2006) Maternal antioxidant intake in pregnancy and wheezing illnesses in children at 2 y of age. Am J Clin Nutr 84:903–911
Prasad AS, Beck FW, Bao B et al (2007) Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation of cytokines and oxidative stress. Am J Clin Nutr 85:837–844
Berger MM, Shenkin A (2007) Trace element requirements in critically ill burned patients. J Trace Elem Med Biol 21(Suppl 1):44–48
Fraker PJ, King LE (2004) Reprogramming of the immune system during zinc deficiency. Annu Rev Nutr 24:277–298
Prasad AS (1998) Zinc and immunity. Mol Cell Biochem 188:63–69
Hosea HJ, Rector ES, Taylor CG (2003) Zinc-deficient rats have fewer recent thymic emigrant (CD90+) T lymphocytes in spleen and blood. J Nutr 133:4239–4242
Ibs KH, Rink L (2003) Zinc-altered immune function. J Nutr 133:1452S–1456S
Prasad AS (2000) Effects of zinc deficiency on Th1 and Th2 cytokine shifts. J Infect Dis 182(Suppl 1):S62–S68
Adler HS, Steinbrink K (2007) Tolerogenic dendritic cells in health and disease: friend and foe!. Eur J Dermatol 17:476–491
Banchereau J, Briere F, Caux C et al (2000) Immunobiology of dendritic cells. Annu Rev Immunol 18:767–811
van Duivenvoorde LM, Han WG, Bakker AM et al (2007) Immunomodulatory dendritic cells inhibit Th1 responses and arthritis via different mechanisms. J Immunol 179:1506–1515
Steinbrink K, Mahnke K, Grabbe S et al (2009) Myeloid dendritic cell: from sentinel of immunity to key player of peripheral tolerance? Hum Immunol 70:289–293
Cerovic V, McDonald V, Nassar MA et al (2009) New insights into the roles of dendritic cells in intestinal immunity and tolerance. Int Rev Cell Mol Biol 272:33–105
Edelman SM, Kasper DL (2008) Symbiotic commensal bacteria direct maturation of the host immune system. Curr Opin Gastroenterol 24:720–724
Rescigno M, Lopatin U, Chieppa M (2008) Interactions among dendritic cells, macrophages, and epithelial cells in the gut: implications for immune tolerance. Curr Opin Immunol 20:669–675
Kitamura H, Morikawa H, Kamon H et al (2006) Toll-like receptor-mediated regulation of zinc homeostasis influences dendritic cell function. Nat Immunol 7:971–977
Tabas I (1999) Secretory sphingomyelinase. Chem Phys Lipids 102:123–130
Carpinteiro A, Dumitru C, Schenck M et al (2008) Ceramide-induced cell death in malignant cells. Cancer Lett 264:1–10
Grassme H, Becker KA, Zhang Y et al (2008) Ceramide in bacterial infections and cystic fibrosis. Biol Chem 389:1371–1379
Jana A, Hogan EL, Pahan K (2009) Ceramide and neurodegeneration: susceptibility of neurons and oligodendrocytes to cell damage and death. J Neurol Sci 278:5–15
Lang F, Gulbins E, Lerche H et al (2008) Eryptosis, a window to systemic disease. Cell Physiol Biochem 22:373–380
Perrotta C, De Palma C, Clementi E (2008) Nitric oxide and sphingolipids: mechanisms of interaction and role in cellular pathophysiology. Biol Chem 389:1391–1397
Smith EL, Schuchman EH (2008) The unexpected role of acid sphingomyelinase in cell death and the pathophysiology of common diseases. FASEB J 22:3419–3431
Horinouchi K, Erlich S, Perl DP et al (1995) Acid sphingomyelinase deficient mice: a model of types A and B Niemann-Pick disease. Nat Genet 10:288–293
Lin T, Genestier L, Pinkoski MJ et al (2000) Role of acidic sphingomyelinase in Fas/CD95-mediated cell death. J Biol Chem 275:8657–8663
Inaba K, Inaba M, Romani N et al (1992) Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med 176:1693–1702
Shumilina E, Zahir N, Xuan NT et al (2007) Phosphoinositide 3-kinase dependent regulation of Kv channels in dendritic cells. Cell Physiol Biochem 20:801–808
Wang K, Mahmud H, Foller M et al (2008) Lipopeptides in the triggering of erythrocyte cell membrane scrambling. Cell Physiol Biochem 22:381–386
Berridge MV, Tan AS (1993) Characterization of the cellular reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT): subcellular localization, substrate dependence, and involvement of mitochondrial electron transport in MTT reduction. Arch Biochem Biophys 303:474–482
Orlov SN, Thorin-Trescases N, Pchejetski D et al (2004) Na+/K+ pump and endothelial cell survival: [Na+]i/[K+]i-independent necrosis triggered by ouabain, and protection against apoptosis mediated by elevation of [Na+]i. Pflugers Arch 448:335–345
Rudolf E, Cervinka M (2008) External zinc stimulates proliferation of tumor Hep-2 cells by active modulation of key signaling pathways. J Trace Elem Med Biol 22:149–161
Franklin RB, Costello LC (2009) The important role of the apoptotic effects of zinc in the development of cancers. J Cell Biochem 106:750–757
Haase H, Rink L (2009) Functional significance of zinc-related signaling pathways in immune cells. Annu Rev Nutr 29:133–152
Vallee BL, Gibson JG (1948) The zinc content of normal human whole blood, plasma, leucocytes, and erythrocytes. J Biol Chem 176:445–457
Massadeh A, Gharibeh A, Omari K et al (2010) Simultaneous determination of Cd, Pb, Cu, Zn, and Se in human blood of Jordanian smokers by ICP-OES. Biol Trace Elem Res 133:1–11
Blindauer CA, Harvey I, Bunyan KE et al (2009) Structure, properties, and engineering of the major zinc binding site on human albumin. J Biol Chem 284:23116–23124
Outten CE, O’Halloran TV (2001) Femtomolar sensitivity of metalloregulatory proteins controlling zinc homeostasis. Science 292:2488–2492
Falcone S, Perrotta C, De Palma C et al (2004) Activation of acid sphingomyelinase and its inhibition by the nitric oxide/cyclic guanosine 3′,5′-monophosphate pathway: key events in Escherichia coli-elicited apoptosis of dendritic cells. J Immunol 173:4452–4463
Handley ME, Thakker M, Pollara G et al (2005) JNK activation limits dendritic cell maturation in response to reactive oxygen species by the induction of apoptosis. Free Radic Biol Med 38:1637–1652
Lundqvist A, Nagata T, Kiessling R et al (2002) Mature dendritic cells are protected from Fas/CD95-mediated apoptosis by upregulation of Bcl-X(L). Cancer Immunol Immunother 51:139–144
Leverkus M, Walczak H, McLellan A et al (2000) Maturation of dendritic cells leads to up-regulation of cellular FLICE-inhibitory protein and concomitant down-regulation of death ligand-mediated apoptosis. Blood 96:2628–2631
Willems F, Amraoui Z, Vanderheyde N et al (2000) Expression of c-FLIP(L) and resistance to CD95-mediated apoptosis of monocyte-derived dendritic cells: inhibition by bisindolylmaleimide. Blood 95:3478–3482
Nicolo C, Tomassini B, Rippo MR et al (2001) UVB-induced apoptosis of human dendritic cells: contribution by caspase-dependent and caspase-independent pathways. Blood 97:1803–1808
von Bulow V, Rink L, Haase H (2005) Zinc-mediated inhibition of cyclic nucleotide phosphodiesterase activity and expression suppresses TNF-alpha and IL-1 beta production in monocytes by elevation of guanosine 3′,5′-cyclic monophosphate. J Immunol 175:4697–4705
Telford WG, Fraker PJ (1995) Preferential induction of apoptosis in mouse CD4+CD8+alpha beta TCRloCD3 epsilon lo thymocytes by zinc. J Cell Physiol 164:259–270
Kolenko VM, Uzzo RG, Dulin N et al (2001) Mechanism of apoptosis induced by zinc deficiency in peripheral blood T lymphocytes. Apoptosis 6:419–429
Mann JJ, Fraker PJ (2005) Zinc pyrithione induces apoptosis and increases expression of Bim. Apoptosis 10:369–379
Weiss JH, Sensi SL (2000) Ca2+-Zn2+ permeable AMPA or kainate receptors: possible key factors in selective neurodegeneration. Trends Neurosci 23:365–371
Weiss JH, Sensi SL, Koh JY (2000) Zn(2+): a novel ionic mediator of neural injury in brain disease. Trends Pharmacol Sci 21:395–401
Ostrakhovitch EA, Cherian MG (2005) Role of p53 and reactive oxygen species in apoptotic response to copper and zinc in epithelial breast cancer cells. Apoptosis 10:111–121
Klein C, Creach K, Irintcheva V et al (2006) Zinc induces ERK-dependent cell death through a specific Ras isoform. Apoptosis 11:1933–1944
Acknowledgments
The authors gratefully acknowledge the meticulous preparation of the manuscript by Lejla Subasic and Tanja Loch. This work was supported by the Deutsche Forschungsgemeinschaft (SFB 766).
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The authors declare that they have no conflict of interest.
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Shumilina, E., Xuan, N.T., Schmid, E. et al. Zinc induced apoptotic death of mouse dendritic cells. Apoptosis 15, 1177–1186 (2010). https://doi.org/10.1007/s10495-010-0520-x
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DOI: https://doi.org/10.1007/s10495-010-0520-x