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Gene expression analysis suggests that 1,25-dihydroxyvitamin D₃ reverses experimental autoimmune encephalomyelitis by stimulating inflammatory cell apoptosis

¹ Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706
² Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706
³ Department of Horticulture and Statistics, University of Wisconsin-Madison, Madison, Wisconsin 53706
⁴ Department of Genetics and Medical Genetics, University of Wisconsin-Madison, Madison, Wisconsin 53706

Multiple sclerosis (MS) is a debilitating autoimmune disease of the central nervous system (CNS) that develops in genetically susceptible individuals who are exposed to undefined environmental risk factors. Epidemiological, genetic, and biological evidence suggests that insufficient vitamin D may be an MS risk factor. However, little is known about how vitamin D might be protective in MS. We hypothesized that 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] might regulate gene expression patterns in a manner that would resolve inflammation. To test this hypothesis, experimental autoimmune encephalomyelitis (EAE) was induced in mice, 1,25-(OH)₂D₃ or a placebo was administered, and 6 h later, DNA microarray hybridization was performed with spinal cord RNA to analyze the gene expression patterns. At this time, clinical, histopathological, and biological studies showed that the two groups did not differ in EAE disease, but changes in several 1,25-(OH)₂D₃-responsive genes indicated that the 1,25-(OH)₂D₃ had reached the CNS. Compared with normal mice, placebo-treated mice with EAE showed increased expression of many immune system genes, confirming the acute inflammation. When 1,25-(OH)₂D₃ was administered, several genes like glial fibrillary acidic protein and eukaryotic initiation factor 2 kinase 4, whose expression increased or decreased with EAE, returned to homeostatic levels. Also, two genes with pro-apoptotic functions, calpain-2 and caspase-8-associated protein, increased significantly. A terminal deoxynucleotidyl transferase-mediated dUTP nicked end labeling study detected increased nuclear fragmentation in the 1,25-(OH)₂D₃-treated samples, confirming increased apoptosis. Together, these results suggest that sensitization of inflammatory cells to apoptotic signals may be one mechanism by which the 1,25-(OH)₂D₃ resolved EAE.

vitamin D; multiple sclerosis; autoimmune disease; DNA microarray

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