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* Department of Nutritional Sciences and
Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin, Madison, WI 53706; and
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226
Multiple sclerosis (MS) results from an aberrant, neuroantigen-specific, T cell-mediated autoimmune response. Because MS prevalence and severity decrease sharply with increasing sunlight exposure, and sunlight supports vitamin D3 synthesis, we proposed that vitamin D3 and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) may protect against MS. In support of this hypothesis, 1,25-(OH)2D3 strongly inhibited experimental autoimmune encephalomyelitis (EAE). This inhibition required lymphocytes other than the encephalitogenic T cells. In this study, we tested the hypothesis that 1,25-(OH)2D3 might inhibit EAE through the action of IL-10-producing regulatory lymphocytes. We report that vitamin D3 and 1,25-(OH)2D3 strongly inhibited myelin oligodendrocyte peptide (MOG35–55)-induced EAE in C57BL/6 mice, but completely failed to inhibit EAE in mice with a disrupted IL-10 or IL-10R gene. Thus, a functional IL-10-IL-10R pathway was essential for 1,25-(OH)2D3 to inhibit EAE. The 1,25-(OH)2D3 also failed to inhibit EAE in reciprocal, mixed bone marrow chimeras constructed by transferring IL-10-deficient bone marrow into irradiated wild-type mice and vice versa. Thus, 1,25-(OH)2D3 may be enhancing an anti-inflammatory loop involving hemopoietic cell-produced IL-10 acting on brain parenchymal cells and vice versa. If this interpretation is correct, and humans have a similar bidirectional IL-10-dependent loop, then an IL-10-IL-10R pathway defect could abrogate the anti-inflammatory and neuro-protective functions of sunlight and vitamin D3. In this way, a genetic IL-10-IL-10R pathway defect could interact with an environmental risk factor, vitamin D3 insufficiency, to increase MS risk and severity.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Multiple Sclerosis Society Research Grant RG-3107 and National Institutes of Health Predoctoral Training Grant DK 07665-08 through the Department of Nutritional Sciences (University of Wisconsin, Madison, WI) (to K.M.S).
2 Address correspondence and reprint requests to Dr. Colleen E. Hayes, Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin, 433 Babcock Drive, Madison, WI 53706. E-mail address: hayes{at}biochem.wisc.edu
3 Abbreviations used in this paper: MS, multiple sclerosis, 1,25-(OH)2D3, 1,25-dihydoxyvitamin D3; BM, bone marrow; EAE, experimental autoimmune encephalomyelitis; MBP, myelin basic protein; MOG35–55, myelin oligodendrocytic glycoprotein peptide; VDR, vitamin D receptor.
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