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

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 D3 inhibited experimental autoimmune encephalomyelitis (EAE) in intact female mice, but not in ovariectomized females or males. To learn whether 17 beta-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, 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. The Journal of Immunology, 2009, 183: 3672-3681.