Several studies support a protective effect of
vitamin D on
multiple sclerosis and
experimental allergic encephalomyelitis (EAE), but the mechanisms of these favorable effects are unclear. Our study demonstrates that
sphingosine 1-phosphate (S1P) is upregulated in the serum and spinal cords of EAE rats, but that
vitamin D reverses the upregulation to alleviate
inflammation.
Vitamin D, however, cannot prevent the disease process, suggesting that other factors may be involved. To identify additional factors that might limit
vitamin D efficacy, we assessed the effects of
vitamin D on plasma
gelsolin (pGSN), a regulator of S1P that is downregulated in the CSF of MS patients. Our results show that pGSN is downregulated in the serum of EAE rats, whereas its cellular form, cytoplasmic
gelsolin (cGSN), is upregulated in the spinal cord of EAE rats. Importantly,
vitamin D causes a downregulation of both pGSN and cGSN, which may counteract the positive effects of S1P decrease. Furthermore, 48 and 42 kDa
caspase-3 cleavage products of cGSN are detected in EAE spinal cords, suggesting enhanced apoptotic activity, but these cleaved products undergo a similar decrease upon
vitamin D treatment. To directly test the role of cGSN in the apoptotic process, we performed RNA interference in PC-12, a rat sympathetic nerve cell line. Results verify that cGSN suppresses apoptosis induced by TNF-α. Collectively, these results support a
therapeutic effect of
vitamin D that is derived from its ability to reduce S1P, but is limited by its simultaneous effect in reducing pGSN and cGSN. Based on these observations, we postulate that combined
therapy with recombinant human pGSN and
vitamin D may produce more beneficial effect in treating
multiple sclerosis.