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

• Published in: The Journal of immunology (1950) Vol. 185; no. 8; pp. 4948 - 4958
• Main Authors: Correale, Jorge, Ysrraelit, María C, Gaitán, María I
• Format: Journal Article
• Language: English
• Published: United States 15.10.2010
• Subjects: Adult; Calcitriol - blood; Calcitriol - metabolism; Calcitriol - pharmacology; Cell Proliferation - drug effects; Cytokines - biosynthesis; Enzyme-Linked Immunosorbent Assay; Estradiol - pharmacology; Estrogens - pharmacology; Female; Humans; Immunologic Factors - blood; Immunologic Factors - metabolism; Immunologic Factors - pharmacology; Male; Multiple Sclerosis, Relapsing-Remitting - immunology; Multiple Sclerosis, Relapsing-Remitting - metabolism; Receptors, Estrogen - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Sex Characteristics; T-Lymphocytes - drug effects; T-Lymphocytes - immunology
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1000588

Vitamin D3 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 D3 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 D3-inactivating enzyme, as well as greater binding and internalization of vitamin D3-binding protein, a transporter for vitamin D3 and its metabolites. These gender-based disparities lead to the accumulation of vitamin D3 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 D3 and 17-β estradiol, mediated through estrogen receptor α. Collectively, these results demonstrate estrogen-promoted differences in vitamin D3 metabolism, suggesting a greater protective effect of vitamin D3-based therapeutic strategies in women.