Objectives: Compared to the Dark Agouti (DA), the Albino Oxford (AO) rat strain exhibits lower susceptibility to the induction of experimental autoimmune encephalomyelitis (EAE). Here, we investigated the potential contribution of the heavy metal-binding proteins metallothioneins (MTs) I/II to these effects. Methods: Rats were immunized with bovine brain homogenate emulsified in complete Freund's adjuvant or only with complete Freund's adjuvant. The expression patterns of MTs mRNA and proteins and tissue concentrations of Zn2+ and Cu2+ were estimated in the brain and in the liver on days 7 and 12 after immunization, by real-time PCR, immunohistochemistry and inductively coupled plasma spectrometry, respectively. Additionally, the hepatic transforming growth factor beta and nuclear factor kappa B immunoreactivities were tested. Results: Clinical signs of EAE were not induced in AO rats, but they upregulated the expression of MT I/II proteins in the brain (hippocampus and cerebellum) and in the liver, similarly as DA rats. The transcriptional activation of MT-I occurred, however, only in DA rats, which accumulated also more zinc in the brain and in the liver. In contrast, intact AO rats had greater hepatic MT-I mRNA immunoreactivity and more Cu2+ in the hippocampus. Besides, in immunized AO rats a high upregulation of transforming growth factor beta and nuclear factor kappa B immunoreactivities was found in several hepatic structures (vascular endothelium, Kupffer cells and hepatocytes). Conclusions: Our data show that AO and DA rats differ in constitutive and inductive MT-I gene expression in the brain and in the liver, as well as in the hepatic cytokine profile, suggesting that these mechanisms may contribute to the discrepancy in the susceptibility to EAE.

Pedersen MO, Jensen R, Pedersen DS, Skjolding AD, Hempel C, Maretty L, Penkowa M: Metallothionein-I+II in neuroprotection. BioFactors 2009;35:315-325.
Cousins RJ: Metallothionein - aspects related to copper and zinc metabolism. J Inher Met Dis 1983;6:15-21.
Hidalgo J, Campmany L, Marti O, Armario A: Metallothionein-I induction by stress in specific brain areas. Neurochem Res 1991;16:1145-1148.
Hidalgo J, Penkowa M, Espejo C, Martinez-Caceres EM, Carrasco J, Quintana A, Molinero A, Florit S, Giralt M, Ortega-Aznar A: Expression of metallothionein-I, -II, and -III in Alzheimer disease and animal models of neuroinflammation. Exp Biol Med 2006;231:1450-1458.
West AK, Hidalgo J, Eddins D, Levin ED, Aschner M: Metallothionein in the central nervous system: roles in protection, regeneration and cognition. Neuro Toxicol 2008;29:489-503.
Coyle P, Philcox JC, Carey LC, Rofe AM: Metallothionein: the multipurpose protein. Cell Mol Life Sci 2002;59:627-647.
Cherian MG, Kang YJ: Metallothionein and liver cell regeneration. Exp Biol Med 2006;231:138-144.
Jakovac H, Grebic D, Mrakovcic-Sutic I, Tota M, Broznic D, Marinic J, Tomac J, Milin C, Radosevic-Stasic B: Metallothionein expression and tissue metal kinetics after partial hepatectomy in mice. Biol Trace Elem Res 2006;114:249-268.
Dziegiel P: Expression of metallothioneins in tumor cells. Pol J Pathol 2004;55:3-12.
Maret W: Metallothionein redox biology in the cytoprotective and cytotoxic functions of zinc. Exp Gerontol 2008;43:363-369.
Sato M, Kondoh M: Recent studies on metallothionein: protection against toxicity of heavy metals and oxygen free radicals. Tohoku J Exp Med 2002;196:9-22.
Aschner M, Cherian MG, Klaassen CD, Palmiter RD, Erickson JC, Bush AI: Metallothioneins in brain - the role in physiology and pathology. Toxicol Appl Pharmacol 1997;142:229-242.
Hidalgo J, Penkowa M, Giralt M, Carrasco J, Molinero A: Metallothionein expression and oxidative stress in the brain. Methods Enzymol 2002;348:238-249.
Manso Y, Adlard PA, Carrasco J, Vasak M, Hidalgo J: Metallothionein and brain inflammation. J Biol Inorg Chem 2011;16:1103-1113.
Penkowa M, Espejo C, Ortega-Aznar A, Hidalgo J, Montalban X, Martínez Cáceres EM: Metallothionein expression in the central nervous system of multiple sclerosis patients. Cell Mol Life Sci (CMLS) 2003;60:1258-1266.
Penkowa M, Hidalgo J: Metallothionein I+II expression and their role in experimental autoimmune encephalomyelitis. Glia 2000;32:247-263.
Penkowa M, Hidalgo J: Metallothionein treatment reduces proinflammatory cytokines IL-6 and TNF-alpha and apoptotic cell death during experimental autoimmune encephalomyelitis (EAE). Exp Neurol 2001;170:1-14.
Penkowa M, Hidalgo J: Treatment with metallothionein prevents demyelination and axonal damage and increases oligodendrocyte precursors and tissue repair during experimental autoimmune encephalomyelitis. J Neurosci Res 2003;72:574-586.
Espejo C, Penkowa M, Demestre M, Montalban X, Martínez Cáceres EM: Time course expression of CNS inflammatory, neurodegenerative tissue repair markers and metallothioneins during experimental autoimmune encephalomyelitis. Neurosci 2005;132:1135-1149.
Jakovac H, Grebic D, Tota M, Barac-Latas V, Mrakovcic-Sutic I, Milin C, Radosevic Stasic B: Time-course expression of metallothioneins and tissue metals in chronic relapsing form of experimental autoimmune encephalomyelitis. Histol Histopathol 2011;26:233-245.
Swanborg RH: Experimental autoimmune encephalomyelitis in the rat: lessons in Tcell immunology and autoreactivity. Immunol Rev 2001;184:129-135.
Batoulis H, Addicks K, Kuerten S: Emerging concepts in autoimmune encephalomyelitis beyond the CD4/TH1 paradigm. Ann Anat Anatomischer Anzeiger 2010;192:179-193.
Lassmann H: Axonal and neuronal pathology in multiple sclerosis: what have we learnt from animal models. Exp Neurol 2010;225:2-8.
Wekerle H: Lessons from multiple sclerosis: models, concepts, observations. Ann Rheum Dis 2008;67:iii 56-60.
Wick G, Hu Y, Schwarz S, Kroemer G: Immunoendocrine communication via the hypothalamo-pituitary-adrenal axis in autoimmune diseases. End Rev 1993;14:539563.
Besedovsky HO, del Rey A: Immune-neuro-endocrine interactions: facts and hypotheses. End Rev 1996;17:64-102.
Sternberg EM: Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol 2006;6:318-328.
Mostarica-Stojkovic M, Ejdus-Konstantinovic L, Kostic M, Lukic ML: Resistance to the induction of T cell-mediated autoimmunity correlates with lower IL 2 production. Adv Exp Med Biol 1985;186:713-720.
Muhvic D, Barac-Latas V, Rukavina D, Radosevic-Stasic B: Induction of experimental allergic encephalomyelitis in a low-susceptible Albino Oxford rat strain by somatostatin analogue SMS 201-995. Neuroimmunomodulation 2005;12:20-28.
Markovic M, Miljkovic D, Momcilovic M, Popadic D, Miljkovic Z, Savic E, Ramic Z, Mostarica Stojkovic M: Strain difference in susceptibility to experimental autoimmune encephalomyelitis in rats correlates with TH1 and TH17-inducing cytokine profiles. Mol Immunol 2009;47:141-146.
Mensah-Brown EP, Shahin A, Al Shamisi M, Lukic ML: Early influx of macrophages determines susceptibility to experimental allergic encephalomyelitis in Dark Agouti (DA) rats. J Neuroimmunol 2011;232:68-74.
Miljkovic D, Stanojevic Z, Momcilovic M, Odoardi F, Flugel A, Mostarica-Stojkovic M: CXCL12 expression within the CNS contributes to the resistance against experimental autoimmune encephalomyelitis in Albino Oxford rats. Immunobiology 2011;216:979987.
Andrews GK: Regulation of metallothionein gene expression by oxidative stress and metal ions. Biochem Pharmacol 2000;59:95-104.
Inoue K, Takano H, Shimada A, Satoh M: Metallothionein as an anti-inflammatory mediator. Mediators Inflamm 2009, DOI: 10.1155/2009/101659.
Penkowa M: Metallothioneins are multipurpose neuroprotectants during brain pathology. FEBS J 2006;273:1857-1870.
del Rey A, Besedovsky HO: The cytokine-HPA axis circuit contributes to prevent or moderate autoimmune processes. Zeitschrift Rheumat 2000;59:II/31-35.
Wick G, Sgonc R, Lechner O: Neuroendocrine-immune disturbances in animal models with spontaneous autoimmune diseases. Ann NY Acad Sci 1998;840:591598.
Besedovsky HO, del Rey A: The cytokine-HPA axis feed-back circuit. Zeitschrift Rheumat 2000;59:II/26-30.
Garcia-Bueno B, Caso JR, Leza JC: Stress as a neuroinflammatory condition in brain: damaging and protective mechanisms. Neurosci Biobehav Rev 2008;32:1136-1151.
Chrousos GP: Organization and integration of the endocrine system. Sleep Med Clin 2007;2:125-145.
Stefferl A, Linington C, Holsboer F, Reul JM: Susceptibility and resistance to experimental allergic encephalomyelitis: relationship with hypothalamic-pituitary-adrenocortical axis responsiveness in the rat. Endocrinol 1999;140:4932-4938.
del Rey A, Besedovsky HO, Sorkin E, Da Prada M, Bondiolotti GP: Sympathetic immunoregulation: difference between high- and low-responder animals. Am J Physiol 1982;242:R30-3R3.
Calogero AE, Sternberg EM, Bagdy G, Smith C, Bernardini R, Aksentijevich S, Wilder RL, Gold PW, Chrousos GP: Neurotransmitter-induced hypothalamic-pituitary-adrenal axis responsiveness is defective in inflammatory disease-susceptible Lewis rats: in vivo and in vitro studies suggesting globally defective hypothalamic secretion of corticotropin-releasing hormone. Neuroendocrinol 1992;55:600-608.
Hidalgo J, Belloso E, Hernandez J, Gasull T, Molinero A: Role of glucocorticoids on rat brain metallothionein-I and -III response to stress. Stress 1997;1:231-240.
Besedovsky HO, del Rey A: Regulating inflammation by glucocorticoids. Nat Immunol 2006;7:537.
Carrier Y, Yuan J, Kuchroo VK, Weiner HL: Th3 cells in peripheral tolerance. I. Induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-beta T cell-transgenic mice. J Immunol 2007;178:179-185.
Knolle PA, Gerken G: Local control of the immune response in the liver. Immunol Rev 2000;174:21-34.
Awasthi A, Kuchroo VK: Th17 cells: from precursors to players in inflammation and infection. Int Immunol 2009;21:489-498.
Aranami T, Yamamura T: Th17 cells and autoimmune encephalomyelitis (EAE/MS). Allergol Int 2008;57:115-120.
Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR: IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nature Immunol 2007;8:967-974.
Oukka M: Interplay between pathogenic Th17 and regulatory T cells. Ann Rheum Dis 2007;66:iii 87-90.
Zhang X, Reddy J, Ochi H, Frenkel D, Kuchroo VK, Weiner HL: Recovery from experimental allergic encephalomyelitis is TGF-beta dependent and associated with increases in CD4+LAP+ and CD4+CD25+ T cells. Int Immunol 2006;18:495-503.
Xie L, Li XK, Funeshima-Fuji N, Kimura H, Matsumoto Y, Isaka Y, Takahara S: Amelioration of experimental autoimmune encephalomyelitis by curcumin treatment through inhibition of IL-17 production. Int Immunopharmacol 2009;9:575-581.
Diehl L, Schurich A, Grochtmann R, Hegenbarth S, Chen L, Knolle PA: Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance. Hepatology 2008;47:296-305.
Böttcher JP, Knolle PA, Stabenow D: Mechanisms balancing tolerance and immunity in the liver. Digest Dis 2011;29:384-390.
Hoffman BE, Herzog RW: Coaxing the liver into preventing autoimmune disease in the brain. J Clin Invest 2008;118:3271-3273.
Luth S, Huber S, Schramm C, Buch T, Zander S, Stadelmann C, Bruck W, Wraith DC, Herkel J, Lohse AW: Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs. J Clin Invest 2008;118:3403-3410.
Bell SG, Vallee BL: The metallothionein/thionein system: an oxidoreductive metabolic zinc link. Chembiochem 2009;10:55-62.
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