1,25-dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking

Multiple sclerosis (MS) is a complex neurodegenerative disease whose pathogenesis involves genetic and environmental risk factors leading to an aberrant, neuroantigen-specific, CD4(+) T cell-mediated autoimmune response. In support of the hypothesis that vitamin D-3 may reduce MS risk and severity, we found that vitamin D3 and 1,25-dihydroxyvitamin D3 (1,25-(OH)(2)D-3) inhibited induction of experimental autoimmune encephalomyelitis (EAE), an MS model. To investigate how 1,25-(OH)(2)D-3 could carry out anti-inflammatory functions, we administered 1,25-(OH)(2)D-3 or a placebo to mice with EAE, and subsequently analyzed clinical disease, chemokines, inducible nitric oxide synthase (NOS), and recruitment of dye-labeled monocytes. The 1,25-(OH)(2)D-3 treatment significantly reduced clinical EAE severity within 3 days. Sharp declines in chemokines, inducible NOS, and CD11b(+) monocyte recruitment into the central nervous system (CNS) preceded this clinical disease abatement in the 1,25-(OH)(2)D-3-treated animals. The 1,25-(OH)(2)D-3 did not directly and rapidly inhibit chemokine synthesis in vivo or in vitro. Rather, the 1,25-(OH)(2)D-3 rapidly stimulated activated CD4(+) T cell apoptosis in the CNS and spleen. Collectively, these results support a model wherein inflammation stimulates a natural anti-inflammatory feedback loop. The activated inflammatory cells produce 1,25-(OH)(2)D-3, and this hormone subsequently enhances the apoptotic death of inflammatory CD4(+)T cells, removing the driving force for continued inflammation. In this way, the sunlight-derived hormone could reduce the risk of chronic CNS inflammation and autoimmune-mediated neurodegenerative disease. (C) 2007 Wiley-Liss, Inc.