Gender Differences in 1,25 Dihydroxyvitamin D3 Immunomodulatory Effects in Multiple Sclerosis Patients and Healthy Subjects

Vitamin D-3 is best known as a calcium homeostasis modulator; however, it also has immune-modulating potential. In this study, we demonstrated that immunomodulatory effects of vitamin D-3 are significantly stronger in females than in males in multiple sclerosis patients, as well as in healthy subjects. Inhibition of self-reactive T cell proliferation and reduction in IFN-gamma- and IL-17-secreting cell numbers were considerably greater in females. Furthermore, the increase in IL-10-secreting and CD4(+)CD25(+) FoxP3(+) regulatory T cell numbers were also greater in females. In parallel with these findings, female subjects had fewer CYP24A1 transcripts encoding the 1,25-dihydroxyvitamin D-3-inactivating enzyme, as well as greater binding and internalization of vitamin D-3-binding protein, a transporter for vitamin D-3 and its metabolites. These gender-based disparities lead to the accumulation of vitamin D-3 and its metabolites in target cells from female subjects and result in a more potent anti-inflammatory effect. Interestingly, 17-beta estradiol reproduced these effects on self-reactive T cells and macrophages from male subjects, suggesting a functional synergy between 1,25-dihydroxyvitamin D-3 and 17-beta estradiol, mediated through estrogen receptor a. Collectively, these results demonstrate estrogen-promoted differences in vitamin D-3 metabolism, suggesting a greater protective effect of vitamin D-3-based therapeutic strategies in women. The Journal of Immunology, 2010, 185: 4948-4958.