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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901351v1 183/6/3672    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Nashold, F. E. Articles by Hayes, C. E. PubMed PubMed Citation Articles by Nashold, F. E. Articles by Hayes, C. E. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CHOLECALCIFEROL ESTRADIOL

Estrogen Controls Vitamin D₃-Mediated Resistance to Experimental Autoimmune Encephalomyelitis by Controlling Vitamin D₃ Metabolism and Receptor Expression¹

Faye E. Nashold^*, Karen M. Spach, Justin A. Spanier^* and Colleen E. Hayes^2,*

^* Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, WI 53706; and Department of Immunobiology, College of Medicine, University of Vermont, Burlington, VT 05405

Multiple sclerosis (MS) is an autoimmune, neurodegenerative disease with a rapidly increasing female gender bias. MS prevalence decreases with increasing sunlight exposure, supporting our hypothesis that the sunlight-dependent hormone 1,25-dihydroxyvitamin D₃ (1,25-(OH)₂D₃) is a natural inhibitor of autoimmune T cell responses in MS. We found that vitamin D₃ inhibited experimental autoimmune encephalomyelitis (EAE) in intact female mice, but not in ovariectomized females or males. To learn whether 17β-estradiol (E₂) is essential for vitamin D₃-mediated protection, ovariectomized female mice were given E₂ or placebo and evaluated for vitamin D₃-mediated EAE resistance. Diestrus-level E₂ implants alone provided no benefit, but they restored vitamin D₃-mediated EAE resistance in the ovariectomized females. Synergy between E₂ and vitamin D₃ occurred through vitamin D₃-mediated enhancement of E₂ synthesis, as well as E₂-mediated enhancement of vitamin D receptor expression in the inflamed CNS. In males, E₂ implants did not enable vitamin D₃ to inhibit EAE. The finding that vitamin D₃-mediated protection in EAE is female-specific and E₂-dependent suggests that declining vitamin D₃ supplies due to sun avoidance might be contributing to the rapidly increasing female gender bias in MS. Moreover, declining E₂ synthesis and vitamin D₃-mediated protection with increasing age might be contributing to MS disease progression in older women.

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 Research Grant RG3107 from the National Multiple Sclerosis Society.

² Address correspondence and reprint requests to Dr. Colleen E. Hayes, Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, 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-dihydroxyvitamin D₃; 25-(OH)D₃, 25-hydroxyvitamin D₃; C_t, threshold PCR cycle; E₂, 17β-estradiol; EAE, experimental autoimmune encephalomyelitis; ER, estrogen receptor; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; OVX, ovariectomized; SHAM, sham-operated; VDR, vitamin D receptor.