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Mediators of Inflammation
Volume 2009, Article ID 729172, 9 pages
http://dx.doi.org/10.1155/2009/729172
Review Article

Evidence for a Potential Role of Metallothioneins in Inflammatory Bowel Diseases

Department of Gastroenterology, Ghent University, De Pintelaan 185, 9000 Gent, Belgium

Received 26 January 2009; Accepted 3 July 2009

Academic Editor: Donna-Marie McCafferty

Copyright © 2009 Anouk Waeytens et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. B. L. Vallee, “Introduction to metallothionein,” Methods in Enzymology, vol. 205, pp. 3–7, 1991. View at Google Scholar
  2. Y. Kojima, C. Berger, B. L. Vallee, and J. H. R. Kagi, “Amino-acid sequence of equine renal metallothionein-1B,” Proceedings of the National Academy of Sciences of the United States of America, vol. 73, no. 10, pp. 3413–3417, 1976. View at Google Scholar
  3. D. Laukens, A. Waeytens, P. De Bleser, C. Cuvelier, and M. De Vos, “Metallothionein expression under normal and pathological conditions: mechanisms of gene regulation based on in silico promoter analysis,” Critical Reviews in Eukaryotic Gene Expression, vol. 19, no. 4, pp. 301–317, 2009. View at Google Scholar
  4. M. Karin, R. L. Eddy, W. M. Henry, L. L. Haley, M. G. Byers, and T. B. Shows, “Human metallothionein genes are clustered on chromosome 16,” Proceedings of the National Academy of Sciences of the United States of America, vol. 81, no. 17, pp. 5494–5498, 1984. View at Google Scholar
  5. P. Coyle, J. C. Philcox, L. C. Carey, and A. M. Rofe, “Metallothionein: the multipurpose protein,” Cellular and Molecular Life Sciences, vol. 59, no. 4, pp. 627–647, 2002. View at Publisher · View at Google Scholar
  6. S. Tsuji, H. Kobayashi, Y. Uchida, Y. Ihara, and T. Miyatake, “Molecular cloning of human growth inhibitory factor cDNA and its down-regulation in Alzheimer's disease,” The EMBO Journal, vol. 11, no. 13, pp. 4843–4850, 1992. View at Google Scholar
  7. J. G. Hoey, S. H. Garrett, M. A. Sens, J. H. Todd, and D. A. Sens, “Expression of MT-3 mRNA in human kidney, proximal tubule cell cultures, and renal cell carcinoma,” Toxicology Letters, vol. 92, no. 2, pp. 149–160, 1997. View at Publisher · View at Google Scholar
  8. P. Moffatt and C. Séguin, “Expression of the gene encoding metallothionein-3 in organs of the reproductive system,” DNA and Cell Biology, vol. 17, no. 6, pp. 501–510, 1998. View at Google Scholar
  9. C. J. Quaife, S. D. Findley, J. C. Erickson et al., “Induction of a new metallothionein isoform (MT-IV) occurs during differentiation of stratified squamous epithelia,” Biochemistry, vol. 33, no. 23, pp. 7250–7259, 1994. View at Google Scholar
  10. A. T. Miles, G. M. Hawksworth, J. H. Beattie, and V. Rodilla, “Induction, regulation, degradation, and biological significance of mammalian metallothioneins,” Critical Reviews in Biochemistry and Molecular Biology, vol. 35, no. 1, pp. 35–70, 2000. View at Google Scholar
  11. S. K. De, M. T. McMaster, and G. K. Andrews, “Endotoxin induction of murine metallothionein gene expression,” The Journal of Biological Chemistry, vol. 265, no. 25, pp. 15267–15274, 1990. View at Google Scholar
  12. K. Arizono, S.-I. Kagawa, H. Hamada, and T. Ariyoshi, “Nitric oxide mediated metallothionein induction by lipopolysaccharide,” Research Communications in Molecular Pathology and Pharmacology, vol. 90, no. 1, pp. 49–58, 1995. View at Google Scholar
  13. N. Itoh, K. Kasutani, N. Muto, N. Otaki, M. Kimura, and K. Tanaka, “Blocking effect of anti-mouse interleukin-6 monoclonal antibody and glucocorticoid receptor antagonist, RU38486, on metallothionein-inducing activity of serum from lipopolysaccharide-treated mice,” Toxicology, vol. 112, no. 1, pp. 29–36, 1996. View at Publisher · View at Google Scholar
  14. R. J. Cousins and A. S. Leinart, “Tissue-specific regulation of zinc metabolism and metallothionein genes by interleukin 1,” The FASEB Journal, vol. 2, no. 13, pp. 2884–2890, 1988. View at Google Scholar
  15. J. J. Schroeder and R. J. Cousins, “Interleukin 6 regulates metallothionein gene expression and zinc metabolism in hepatocyte monolayer cultures,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 8, pp. 3137–3141, 1990. View at Google Scholar
  16. M. Sato, M. Sasaki, and H. Hojo, “Differential induction of metallothionein synthesis by interleukin-6 and tumor necrosis factor-α in rat tissues,” International Journal of Immunopharmacology, vol. 16, no. 2, pp. 187–195, 1994. View at Google Scholar
  17. Y. Ren and A. Smith, “Mechanism of metallothionein gene regulation by heme-hemopexin—roles of protein kinase C, reactive oxygen species, and cis-acting elements,” The Journal of Biological Chemistry, vol. 270, no. 41, pp. 23988–23995, 1995. View at Publisher · View at Google Scholar
  18. G. K. Andrews, “Regulation of metallothionein gene expression by oxidative stress and metal ions,” Biochemical Pharmacology, vol. 59, no. 1, pp. 95–104, 2000. View at Publisher · View at Google Scholar
  19. C. Haton, A. Francois, M. Vandamme, J. Wysocki, N. M. Griffiths, and M. Benderitter, “Imbalance of the antioxidant network of mouse small intestinal mucosa after radiation exposure,” Radiation Research, vol. 167, no. 4, pp. 445–453, 2007. View at Publisher · View at Google Scholar · View at PubMed
  20. M. Kondoh, N. Imada, K. Kamada et al., “Property of metallothionein as a Zn pool differs depending on the induced condition of metallothionein,” Toxicology Letters, vol. 142, no. 1-2, pp. 11–18, 2003. View at Publisher · View at Google Scholar
  21. P. Palumaa, E. Eriste, O. Njunkova, L. Pokras, H. Jornvall, and R. Sillard, “Brain-specific metallothionein-3 has higher metal-binding capacity than ubiquitous metallothioneins and binds metals noncooperatively,” Biochemistry, vol. 41, no. 19, pp. 6158–6163, 2002. View at Publisher · View at Google Scholar
  22. L. Tio, L. Villarreal, S. Atrian, and M. Capdevila, “Functional differentiation in the mammalian metallothionein gene family—metal binding features of mouse MT4 and comparison with its paralog MT1,” The Journal of Biological Chemistry, vol. 279, no. 23, pp. 24403–24413, 2004. View at Publisher · View at Google Scholar · View at PubMed
  23. C. J. Schmidt and D. H. Hamer, “Cell specificity and an effect of ras on human metallothionein gene expression,” Proceedings of the National Academy of Sciences of the United States of America, vol. 83, no. 10, pp. 3346–3350, 1986. View at Google Scholar
  24. N. Jahroudi, R. Foster, J. Price-Haughey, G. Beitel, and L. Gedamu, “Cell-type specific and differential regulation of the human metallothionein genes. Correlation with DNA methylation and chromatin structure,” The Journal of Biological Chemistry, vol. 265, no. 11, pp. 6506–6511, 1990. View at Google Scholar
  25. L.-J. Jiang, W. Maret, and B. L. Vallee, “The ATP-metallothionein complex,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 16, pp. 9146–9149, 1998. View at Publisher · View at Google Scholar
  26. T. Matsui, “Zinc deficiency in Crohn's disease,” Journal of Gastroenterology, vol. 33, no. 6, pp. 924–925, 1998. View at Publisher · View at Google Scholar
  27. J. Goh and C. A. O'Morain, “Review article: nutrition and adult inflammatory bowel disease,” Alimentary Pharmacology & Therapeutics, vol. 17, no. 3, pp. 307–320, 2003. View at Publisher · View at Google Scholar
  28. C. Ainley, J. Cason, B. M. Slavin, R. A. Wolstencroft, and R. P. H. Thompson, “The influence of zinc status and malnutrition on immunological function in Crohn's disease,” Gastroenterology, vol. 100, no. 6, pp. 1616–1625, 1991. View at Google Scholar
  29. A. H. Shankar and A. S. Prasad, “Zinc and immune function: the biological basis of altered resistance to infection,” American Journal of Clinical Nutrition, vol. 68, no. 2, pp. 447S–463S, 1998. View at Google Scholar
  30. E. Cario, S. Jung, J. D. Harder et al., “Effects of exogenous zinc supplementation on intestinal epithelial repair in vitro,” European Journal of Clinical Investigation, vol. 30, no. 5, pp. 419–428, 2000. View at Publisher · View at Google Scholar
  31. W. Maret, “Zinc coordination environments in proteins as redox sensors and signal transducers,” Antioxidants & Redox Signaling, vol. 8, no. 9-10, pp. 1419–1441, 2006. View at Publisher · View at Google Scholar · View at PubMed
  32. S. Vasto, E. Mocchegiani, M. Malavolta et al., “Zinc and inflammatory/immune response in aging,” Annals of the New York Academy of Sciences, vol. 1100, pp. 111–122, 2007. View at Publisher · View at Google Scholar · View at PubMed
  33. A. S. Prasad, “Clinical, immunological, anti-inflammatory and antioxidant roles of zinc,” Experimental Gerontology, vol. 43, no. 5, pp. 370–377, 2008. View at Publisher · View at Google Scholar · View at PubMed
  34. M. Comalada and M. P. Peppelenbosch, “Impaired innate immunity in Crohn's disease,” Trends in Molecular Medicine, vol. 12, no. 9, pp. 397–399, 2006. View at Publisher · View at Google Scholar · View at PubMed
  35. M. Jaattela, H. Mouritzen, F. Elling, and L. Bastholm, “A20 zinc finger protein inhibits TNF and IL-1 signaling,” The Journal of Immunology, vol. 156, no. 3, pp. 1166–1173, 1996. View at Google Scholar
  36. A. S. Prasad, B. Bao, F. W. J. Beck, O. Kucuk, and F. H. Sarkar, “Antioxidant effect of zinc in humans,” Free Radical Biology and Medicine, vol. 37, no. 8, pp. 1182–1190, 2004. View at Publisher · View at Google Scholar · View at PubMed
  37. A. S. Prasad, “Effects of zinc deficiency on Th1 and Th2 cytokine shifts,” Journal of Infectious Diseases, vol. 182, no. 3, pp. S62–S68, 2000. View at Google Scholar
  38. D. Raddatz, M. Bockemuhl, and G. Ramadori, “Quantitative measurement of cytokine mRNA in inflammatory bowel disease: relation to clinical and endoscopic activity and outcome,” European Journal of Gastroenterology & Hepatology, vol. 17, no. 5, pp. 547–557, 2005. View at Publisher · View at Google Scholar
  39. J. Sventoraityte, A. Zvirbliene, G. Kiudelis et al., “Immune system alterations in patients with inflammatory bowel disease during remission,” Medicina, vol. 44, no. 1, pp. 27–33, 2008. View at Google Scholar
  40. B.-W. Chen, H.-H. Wang, J.-X. Liu, and X.-G. Liu, “Zinc sulphate solution enema decreases inflammation in experimental colitis in rats,” Journal of Gastroenterology and Hepatology, vol. 14, no. 11, pp. 1088–1092, 1999. View at Publisher · View at Google Scholar
  41. H. H. Luk, J. K. S. Ko, H. S. Fung, and C. H. Cho, “Delineation of the protective action of zinc sulfate on ulcerative colitis in rats,” European Journal of Pharmacology, vol. 443, no. 1–3, pp. 197–204, 2002. View at Publisher · View at Google Scholar
  42. G. C. Sturniolo, W. Fries, E. Mazzon, V. Di Leo, M. Barollo, and R. D'Inca, “Effect of zinc supplementation on intestinal permeability in experimental colitis,” Journal of Laboratory and Clinical Medicine, vol. 139, no. 5, pp. 311–315, 2002. View at Publisher · View at Google Scholar
  43. T. Ohkawara, H. Takeda, K. Kato et al., “Polaprezinc (N-(3-aminopropionyl)-L-histidinato zinc) ameliorates dextran sulfate sodium-induced colitis in mice,” Scandinavian Journal of Gastroenterology, vol. 40, no. 11, pp. 1321–1327, 2005. View at Publisher · View at Google Scholar
  44. C. D. Tran, J. M. Ball, S. Sundar, P. Coyle, and G. S. Howarth, “The role of zinc and metallothionein in the dextran sulfate sodium-induced colitis mouse model,” Digestive Diseases and Sciences, vol. 52, no. 9, pp. 2113–2121, 2007. View at Publisher · View at Google Scholar · View at PubMed
  45. V. Di Leo, R. D'Inca, M. Barollo et al., “Effect of zinc supplementation on trace elements and intestinal metallothionein concentrations in experimental colitis in the rat,” Digestive and Liver Disease, vol. 33, no. 2, pp. 135–139, 2001. View at Google Scholar
  46. T. P. J. Mulder, A. van der Sluys Veer, H. W. Verspaget et al., “Effect of oral zinc supplementation on metallothionein and superoxide dismutase concentrations in patients with inflammatory bowel disease,” Journal of Gastroenterology and Hepatology, vol. 9, no. 5, pp. 472–477, 1994. View at Google Scholar
  47. G. C. Sturniolo, V. Di Leo, A. Ferronato, A. D'Odorico, and R. D'Incà, “Zinc supplementation tightens “Leaky Gut” in Crohn's disease,” Inflammatory Bowel Diseases, vol. 7, no. 2, pp. 94–98, 2001. View at Google Scholar
  48. J. C. Lambert, Z. Zhou, L. Wang, Z. Song, C. J. McClain, and Y. J. Kang, “Preservation of intestinal structural integrity by zinc is independent of metallothionein in alcohol-intoxicated mice,” American Journal of Pathology, vol. 164, no. 6, pp. 1959–1966, 2004. View at Google Scholar
  49. A. B. Abdel-Mageed and K. C. Agrawal, “Activation of nuclear factor κB: potential role in metallothionein-mediated mitogenic response,” Cancer Research, vol. 58, no. 11, pp. 2335–2338, 1998. View at Google Scholar
  50. C. H. Kim, J. H. Kim, J. Lee, and Y. S. Ahn, “Zinc-induced NF-κB inhibition can be modulated by changes in the intracellular metallothionein level,” Toxicology and Applied Pharmacology, vol. 190, no. 2, pp. 189–196, 2003. View at Publisher · View at Google Scholar
  51. Y. Kabe, K. Ando, S. Hirao, M. Yoshida, and H. Handa, “Redox regulation of NF-κB activation: distinct redox regulation between the cytoplasm and the nucleus,” Antioxidants & Redox Signaling, vol. 7, no. 3-4, pp. 395–403, 2005. View at Publisher · View at Google Scholar · View at PubMed
  52. M. Kanekiyo, N. Itoh, A. Kawasaki, K. Matsuda, T. Nakanishi, and K. Tanaka, “Metallothionein is required for zinc-induced expression of the macrophage colony stimulating factor gene,” Journal of Cellular Biochemistry, vol. 86, no. 1, pp. 145–153, 2002. View at Publisher · View at Google Scholar · View at PubMed
  53. A. Sakurai, S. Hara, N. Okano, Y. Kondo, J.-I. Inoue, and N. Imura, “Regulatory role of metallothionein in NF-κB activation,” FEBS Letters, vol. 455, no. 1-2, pp. 55–58, 1999. View at Publisher · View at Google Scholar
  54. M. Kanekiyo, N. Itoh, A. Kawasaki et al., “Metallothionein modulates lipopolysaccharide-stimulated tumour necrosis factor expression in mouse peritoneal macrophages,” Biochemical Journal, vol. 361, no. 2, pp. 363–369, 2002. View at Publisher · View at Google Scholar
  55. K. C. Crowthers, V. Kline, C. Giardina, and M. A. Lynes, “Augmented humoral immune function in metallothionein-null mice,” Toxicology and Applied Pharmacology, vol. 166, no. 3, pp. 161–172, 2000. View at Publisher · View at Google Scholar · View at PubMed
  56. H. Takano, K. Inoue, R. Yanagisawa et al., “Protective role of metallothionein in acute lung injury induced by bacterial endotoxin,” Thorax, vol. 59, no. 12, pp. 1057–1062, 2004. View at Publisher · View at Google Scholar · View at PubMed
  57. T. Yamada and M. B. Grisham, “Role of neutrophil-derived oxidants in the pathogenesis of intestinal inflammation,” Klinische Wochenschrift, vol. 69, no. 21–23, pp. 988–994, 1991. View at Google Scholar
  58. Y. Naito, T. Takagi, and T. Yoshikawa, “Molecular fingerprints of neutrophil-dependent oxidative stress in inflammatory bowel disease,” Journal of Gastroenterology, vol. 42, no. 10, pp. 787–798, 2007. View at Publisher · View at Google Scholar · View at PubMed
  59. P. Irato, G. Santovito, E. Piccinni, and V. Albergoni, “Oxidative burst and metallothionein as a scavenger in macrophages,” Immunology and Cell Biology, vol. 79, no. 3, pp. 251–254, 2001. View at Publisher · View at Google Scholar · View at PubMed
  60. I. I. Singer, D. W. Kawka, S. Scott et al., “Expression of inducible nitric oxide synthase and nitrotyrosine in colonic epithelium in inflammatory bowel disease,” Gastroenterology, vol. 111, no. 4, pp. 871–885, 1996. View at Google Scholar
  61. L. Kruidenier, I. Kuiper, C. B. Lamers, and H. W. Verspaget, “Intestinal oxidative damage in inflammatory bowel disease: semi-quantification, localization, and association with mucosal antioxidants,” Journal of Pathology, vol. 201, no. 1, pp. 28–36, 2003. View at Publisher · View at Google Scholar · View at PubMed
  62. A. Rezaie, F. Ghorbani, A. Eshghtork et al., “Alterations in salivary antioxidants, nitric oxide, and transforming growth factor-β1 in relation to disease activity in Crohn's disease patients,” Annals of the New York Academy of Sciences, vol. 1091, pp. 110–122, 2006. View at Publisher · View at Google Scholar · View at PubMed
  63. Y. Dincer, Y. Erzin, S. Himmetoglu, K. N. Gunes, K. Bal, and T. Akcay, “Oxidative DNA damage and antioxidant activity in patients with inflammatory bowel disease,” Digestive Diseases and Sciences, vol. 52, no. 7, pp. 1636–1641, 2007. View at Publisher · View at Google Scholar · View at PubMed
  64. R. Rao, “Oxidative stress-induced disruption of epithelial and endothelial tight junctions,” Frontiers in Bioscience, vol. 13, pp. 7210–7226, 2008. View at Google Scholar
  65. D. Hollander, C. M. Vadheim, E. Brettholz, G. M. Petersen, T. Delahunty, and J. I. Rotter, “Increased intestinal permeability in patients with Crohn's disease and their relatives: a possible etiologic factor,” Annals of Internal Medicine, vol. 105, no. 6, pp. 883–885, 1986. View at Google Scholar
  66. A. Keshavarzian, G. Morgan, S. Sedghi, J. H. Gordon, and M. Doria, “Role of reactive oxygen metabolites in experimental colitis,” Gut, vol. 31, no. 7, pp. 786–790, 1990. View at Google Scholar
  67. J. Segui, M. Gironella, M. Sans et al., “Superoxide dismutase ameliorates TNBS-induced colitis by reducing oxidative stress, adhesion molecule expression, and leukocyte recruitment into the inflamed intestine,” Journal of Leukocyte Biology, vol. 76, no. 3, pp. 537–544, 2004. View at Publisher · View at Google Scholar · View at PubMed
  68. J. Segui, F. Gil, M. Gironella et al., “Down-regulation of endothelial adhesion molecules and leukocyte adhesion by treatment with superoxide dismutase is beneficial in chronic immune experimental colitis,” Inflammatory Bowel Diseases, vol. 11, no. 10, pp. 872–882, 2005. View at Publisher · View at Google Scholar
  69. V. Vasina, M. Broccoli, M. G. Ursino et al., “Effects of the non-peptidyl low molecular weight radical scavenger IAC in DNBS-induced colitis in rats,” European Journal of Pharmacology, vol. 614, no. 1–3, pp. 137–145, 2009. View at Publisher · View at Google Scholar · View at PubMed
  70. I. M. Carroll, J. M. Andrus, J. M. Bruno-Barcena, T. R. Klaenhammer, H. M. Hassan, and D. S. Threadgill, “Anti-inflammatory properties of Lactobacillus gasseri expressing manganese superoxide dismutase using the interleukin 10-deficient mouse model of colitis,” American Journal of Physiology, vol. 293, no. 4, pp. G729–G738, 2007. View at Publisher · View at Google Scholar · View at PubMed
  71. L. Kruidenier, M. E. van Meeteren, I. Kuiper et al., “Attenuated mild colonic inflammation and improved survival from severe DSS-colitis of transgenic Cu/Zn-SOD mice,” Free Radical Biology and Medicine, vol. 34, no. 6, pp. 753–765, 2003. View at Publisher · View at Google Scholar
  72. M. Penkowa and J. Hidalgo, “Metallothionein treatment reduces proinflammatory cytokines IL-6 and TNF-α and apoptotic cell death during experimental autoimmune encephalomyelitis (EAE),” Experimental Neurology, vol. 170, no. 1, pp. 1–14, 2001. View at Publisher · View at Google Scholar · View at PubMed
  73. N. Itoh, H. Shibayama, M. Kanekiyo et al., “Reduced bactericidal activity and nitric oxide production in metallothionein-deficient macrophages in response to lipopolysaccharide stimulation,” Toxicology, vol. 216, no. 2-3, pp. 188–196, 2005. View at Publisher · View at Google Scholar · View at PubMed
  74. H. Y. Jin, Q. Hui, J. Y. Jun et al., “Preliminary studies on the zinc-induced metallothionein protein with antibacterial activity in housefly larvae, Musca domestica,” Acta Biologica Hungarica, vol. 56, no. 3-4, pp. 283–295, 2005. View at Publisher · View at Google Scholar · View at PubMed
  75. K. Tsujikawa, T. Imai, M. Kakutani et al., “Localization of metallothionein in nuclei of growing primary cultured adult rat hepatocytes,” FEBS Letters, vol. 283, no. 2, pp. 239–242, 1991. View at Publisher · View at Google Scholar
  76. W. W. Nagel and B. L. Vallee, “Cell cycle regulation of metallothionein in human colonic cancer cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 2, pp. 579–583, 1995. View at Publisher · View at Google Scholar
  77. M. G. Cherian and Y. J. Kang, “Metallothionein and liver cell regeneration,” Experimental Biology and Medicine, vol. 231, no. 2, pp. 138–144, 2006. View at Google Scholar
  78. C. Schmidt and D. Beyersmann, “Transient peaks in zinc and metallothionein levels during differentiation of 3T3L1 cells,” Archives of Biochemistry and Biophysics, vol. 364, no. 1, pp. 91–98, 1999. View at Publisher · View at Google Scholar · View at PubMed
  79. M. Levadoux-Martin, J. E. Hesketh, J. H. Beattie, and H. M. Wallace, “Influence of metallothionein-1 localization on its function,” Biochemical Journal, vol. 355, no. 2, pp. 473–479, 2001. View at Publisher · View at Google Scholar
  80. M. A. Lynes, K. Zaffuto, D. W. Unfricht, G. Marusov, J. S. Samson, and X. Yin, “The physiological roles of extracellular metallothionein,” Experimental Biology and Medicine, vol. 231, no. 9, pp. 1548–1554, 2006. View at Google Scholar
  81. X. Yin, D. A. Knecht, and M. A. Lynes, “Metallothionein mediates leukocyte chemotaxis,” BMC Immunology, vol. 6, article 21, 2005. View at Publisher · View at Google Scholar · View at PubMed
  82. M. A. Lynes, J. S. Garvey, and D. A. Lawrence, “Extracellular metallothionein effects on lymphocyte activities,” Molecular Immunology, vol. 27, no. 3, pp. 211–219, 1990. View at Publisher · View at Google Scholar
  83. L. A. Borghesi, J. Youn, E. A. Olson, and M. A. Lynes, “Interactions of metallothionein with murine lymphocytes: plasma membrane binding and proliferation,” Toxicology, vol. 108, no. 1-2, pp. 129–140, 1996. View at Publisher · View at Google Scholar
  84. M. A. Lynes, L. A. Borghesi, J. Youn, and E. A. Olson, “Immunomodulatory activities of extracellular metallothionein I. Metallothionein effects on antibody production,” Toxicology, vol. 85, no. 2-3, pp. 161–177, 1993. View at Publisher · View at Google Scholar
  85. J. Youn and M. A. Lynes, “Metallothionein-induced suppression of cytotoxic T lymphocyte function: an important immunoregulatory control,” Toxicological Sciences, vol. 52, no. 2, pp. 199–208, 1999. View at Google Scholar
  86. E. Canpolat and M. A. Lynes, “In vivo manipulation of endogenous metallothionein with a monoclonal antibody enhances T-dependent humoral immune response,” Toxicological Sciences, vol. 62, no. 1, pp. 61–70, 2001. View at Google Scholar
  87. M. Bruwer, K. W. Schmid, K. A. Metz, C. F. Krieglstein, N. Senninger, and G. Schurmann, “Increased expression of metallothionein in inflammatory bowel disease,” Inflammation Research, vol. 50, no. 6, pp. 289–293, 2001. View at Google Scholar
  88. T. P. Dooley, E. V. Curto, S. P. Reddy et al., “Regulation of gene expression in inflammatory bowel disease and correlation with IBD drugs: screening by DNA microarrays,” Inflammatory Bowel Diseases, vol. 10, no. 1, pp. 1–14, 2004. View at Publisher · View at Google Scholar
  89. I. C. Lawrance, C. Fiocchi, and S. Chakravarti, “Ulcerative colitis and Crohn's disease: distinctive gene expression profiles and novel susceptibility candidate genes,” Human Molecular Genetics, vol. 10, no. 5, pp. 445–456, 2001. View at Google Scholar
  90. J. P. Clarkson, M. E. Elmes, B. Jasani, and M. Webb, “Histological demonstration of immunoreactive zinc metallothionein in liver and ileum of rat and man,” Histochemical Journal, vol. 17, no. 3, pp. 343–352, 1985. View at Google Scholar
  91. M. E. Elmes, J. P. Clarkson, and B. Jasani, “Histological demonstration of immunoreactive metallothionein in rat and human tissues,” Experientia Supplementum, vol. 52, pp. 533–537, 1987. View at Google Scholar
  92. E. Ioachim, M. Michael, C. Katsanos, A. Demou, and E. V. Tsianos, “The immunohistochemical expression of metallothionein in inflammatory bowel disease. Correlation with HLA-DR antigen expression, lymphocyte subpopulations and proliferation-associated indices,” Histology and Histopathology, vol. 18, no. 1, pp. 75–82, 2003. View at Google Scholar
  93. L. Kruidenier, I. Kuiper, W. van Duijn et al., “Imbalanced secondary mucosal antioxidant response in inflammatory bowel disease,” Journal of Pathology, vol. 201, no. 1, pp. 17–27, 2003. View at Publisher · View at Google Scholar · View at PubMed
  94. H. S. Oz, T. Chen, W. J. S. de Villiers, and C. J. McClain, “Metallothionein overexpression does not protect against inflammatory bowel disease in a murine colitis model,” Medical Science Monitor, vol. 11, no. 3, pp. BR69–BR73, 2005. View at Google Scholar
  95. T. P. J. Mulder, H. W. Verspaget, A. R. Janssenss, P. A. F. de Bruin, A. S. Pena, and C. B. H. W. Lamers, “Decrease in two intestinal copper/zinc containing proteins with antioxidant function in inflammatory bowel disease,” Gut, vol. 32, no. 10, pp. 1146–1150, 1991. View at Google Scholar
  96. G. C. Sturniolo, C. Mestriner, P. E. Lecis et al., “Altered plasma and mucosal concentrations of trace elements and antioxidants in active ulcerative colitis,” Scandinavian Journal of Gastroenterology, vol. 33, no. 6, pp. 644–649, 1998. View at Publisher · View at Google Scholar
  97. M. Penkowa, C. Espejo, E. M. Martinez-Caceres, C. B. Poulsen, X. Montalban, and J. Hidalgo, “Altered inflammatory response and increased neurodegeneration in metallothionein I+II deficient mice during experimental autoimmune encephalomyelitis,” Journal of Neuroimmunology, vol. 119, no. 2, pp. 248–260, 2001. View at Publisher · View at Google Scholar
  98. C. D. Tran, H. Huynh, M. van den Berg et al., “Helicobacter-induced gastritis in mice not expressing metallothionein-I and II,” Helicobacter, vol. 8, no. 5, pp. 533–541, 2003. View at Publisher · View at Google Scholar
  99. J. Youn, S.-H. Hwang, Z.-Y. Ryoo et al., “Metallothionein suppresses collagen-induced arthritis via induction of TGF-β and down-regulation of proinflammatory mediators,” Clinical and Experimental Immunology, vol. 129, no. 2, pp. 232–239, 2002. View at Publisher · View at Google Scholar
  100. S. Huh, K. Lee, H.-S. Yun, D.-J. Paik, J. M. Kim, and J. Youn, “Functions of metallothionein generating interleukin-10-producing regulatory Cd4+ T cells potentiate suppression of collagen-induced arthritis,” Journal of Microbiology and Biotechnology, vol. 17, no. 2, pp. 348–358, 2007. View at Google Scholar
  101. W. Waelput, D. Broekaert, J. Vandekerckhove, P. Brouckaert, J. Tavernier, and C. Libert, “A mediator role for metallothionein in tumor necrosis factor-induced lethal shock,” Journal of Experimental Medicine, vol. 194, no. 11, pp. 1617–1624, 2001. View at Publisher · View at Google Scholar
  102. K. Leyshon-Sorland, L. Morkrid, and H. E. Rugstad, “Metallothionein: a protein conferring resistance in vitro to tumor necrosis factor,” Cancer Research, vol. 53, no. 20, pp. 4874–4880, 1993. View at Google Scholar
  103. T. Kimura, N. Itoh, M. Takehara et al., “Sensitivity of metallothionein-null mice to LPS/D-galactosamine-induced lethality,” Biochemical and Biophysical Research Communications, vol. 280, no. 1, pp. 358–362, 2001. View at Publisher · View at Google Scholar · View at PubMed
  104. K.-I. Inoue, H. Takano, A. Shimada et al., “Role of metallothionein in coagulatory disturbance and systemic inflammation induced by lipopolysaccharide in mice,” The FASEB Journal, vol. 20, no. 3, pp. 533–535, 2006. View at Publisher · View at Google Scholar · View at PubMed