Active form of vitamin D directly protects the blood-brain barrier in multiple sclerosis

Objectives The active form of vitamin D, 1α,25‐dihydroxyvitamin D 3 (1α,25‐[ OH ] 2 D 3 ), is reported to have protective effects for multiple sclerosis ( MS ), but the precise mechanisms of this effect on MS remain unclear. We hypothesized that 1α,25‐( OH ) 2 D 3 has protective effects on the blood–brain barrier ( BBB ) in MS . Methods The expression of vitamin D receptor in a human brain microvascular endothelial cell line ( HBMEC ) was examined. The effects of 1α,25‐( OH ) 2 D 3 on HBMEC after stimulation with tumor necrosis factor‐α were observed. In addition, we assessed the effects of sera from MS patients, including those in the acute and stable phase of relapse–remitting MS or secondary progressive MS , on the BBB property in the presence or absence of 1α,25‐( OH ) 2 D 3 . Results HBMEC were found to express the vitamin D receptor at both the mRNA and protein level. Pretreatment of HBMEC with 1α,25‐( OH ) 2 D 3 attenuated the decrease of zonula occludens‐1 and claudin‐5, and the increase of intercellular adhesion molecule‐1 ( ICAM ‐1) induced by tumor necrosis factor‐α. In addition, nuclear factor kappa B activation mediated by tumor necrosis factor‐α was decreased after incubation with the activated vitamin D. Furthermore, incubation with 1α,25‐( OH ) 2 D 3 attenuated the increase of vascular cell adhesion molecule‐1 and anti‐phospho‐nuclear factor kappa B in HBMEC after exposure to sera from patients with relapse‐remitting MS and secondary progressive MS , and restored the decrease of zonula occludens‐1 and claudin‐5 in HBMEC after incubation with sera from the acute phase of relapse–remitting MS patients. Conclusions Treatment with 1α,25‐( OH ) 2 D 3 prevents BBB disruption caused by both relapse–remitting MS and secondary progressive MS sera through upregulation of tight junction proteins and downregulation of cell adhesion molecules in HBMEC , suggesting that 1α,25‐( OH ) 2 D 3 might have the direct protective effects on the fragile BBB in MS patients.