title: Estrogen controls vitamin D3-mediated resistance to experimental autoimmune encephalomyelitis by controlling vitamin D3 metabolism and receptor expression.
abstract: 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 D(3) (1,25-(OH)(2)D(3)) is a natural inhibitor of autoimmune T cell responses in MS. We found that vitamin D(3) inhibited experimental autoimmune encephalomyelitis (EAE) in intact female mice, but not in ovariectomized females or males. To learn whether 17beta-estradiol (E(2)) is essential for vitamin D(3)-mediated protection, ovariectomized female mice were given E(2) or placebo and evaluated for vitamin D(3)-mediated EAE resistance. Diestrus-level E(2) implants alone provided no benefit, but they restored vitamin D(3)-mediated EAE resistance in the ovariectomized females. Synergy between E(2) and vitamin D(3) occurred through vitamin D(3)-mediated enhancement of E(2) synthesis, as well as E(2)-mediated enhancement of vitamin D receptor expression in the inflamed CNS. In males, E(2) implants did not enable vitamin D(3) to inhibit EAE. The finding that vitamin D(3)-mediated protection in EAE is female-specific and E(2)-dependent suggests that declining vitamin D(3) supplies due to sun avoidance might be contributing to the rapidly increasing female gender bias in MS. Moreover, declining E(2) synthesis and vitamin D(3)-mediated protection with increasing age might be contributing to MS disease progression in older women.
authors.affiliation: Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA. hayes@biochem.wisc.edu
authors.forename: Faye E
authors.initials: FE
authors.lastname: Nashold
authors.forename: Karen M
authors.initials: KM
authors.lastname: Spach
authors.forename: Justin A
authors.initials: JA
authors.lastname: Spanier
authors.forename: Colleen E
authors.initials: CE
authors.lastname: Hayes
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism; D002762:Cholecalciferol / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology*; D004958:Estradiol / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D004967:Estrogens; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D010052:Ovariectomy; D018167:Receptors, Calcitriol / Q000096:biosynthesis*; D012737:Sex Factors; D014815:Vitamins
chemical_list: D004967:Estrogens; D018167:Receptors, Calcitriol; D014815:Vitamins; D002762:Cholecalciferol; D004958:Estradiol