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-γ- 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-β 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-β estradiol, mediated through estrogen receptor α. 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.
Correale
Jorge
J
Department of Neurology, Raúl Carrea Institute for Neurological Research, Buenos Aires, Argentina. jcorreale@fleni.org.ar
Ysrraelit
María C
MC
Gaitán
María I
MI
D000328:Adult; D002117:Calcitriol / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology* / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012727:Sex Characteristics; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D016207:Cytokines; D004967:Estrogens; D007155:Immunologic Factors; D011960:Receptors, Estrogen; D004958:Estradiol; D002117:Calcitriol