title: Expression of vitamin D receptor and metabolizing enzymes in multiple sclerosis-affected brain tissue.
abstract: Vitamin D deficiency has been implicated as a risk factor for multiple sclerosis (MS), but how vitamin D metabolism affects MS pathophysiology is not understood. We studied the expression of vitamin D receptor (VDR) and related enzymes, including 1,25(OH)(2)D-24-hydroxylase (24-OHase; CYP24A1) and 25(OH)D-1α-hydroxylase (CYP27B1), in CNS tissues of 39 MS patients and 20 controls and in primary human glial cells in vitro. In control and MS normal-appearing white matter (NAWM), nuclear VDR immunostaining was observed in oligodendrocyte-like cells, human leukocyte antigen (HLA)-positive microglia, and glial fibrillary acidic protein-positive astrocytes. There was a 2-fold increase in VDR transcripts in MS NAWM versus control white matter (p = 0.03). In chronic active MS lesions, HLA-positive microglia/macrophages showed nuclear VDR staining; astrocytes showed nuclear and cytoplasmic VDR staining. Staining for 24-OHase was restricted to astrocytes.VDR and CYP27B1 mRNA expressions were increased in active MS lesions versus NAWM (p < 0.01, p = 0.04, respectively). In primary human astrocytes in vitro, the active form of vitamin D, 1,25(OH)(2)D(3), induced upregulation of VDR and CYP24A1. Tumor necrosis factor and interferon-γ upregulated CYP27B1 mRNA in primary human microglia and astrocytes. Increased VDR expression in MS NAWM and inflammatory cytokine-induced amplified expression of VDR and CYP27B1 in chronic active MS lesions suggest increased sensitivity to vitamin D in NAWM and a possible endogenous role for vitamin D metabolism in the suppression of active MS lesions.
authors: Neuroimmunology Research Group, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands. smolders@gmail.com
authors: Joost
authors: J
authors: Smolders
authors: Karianne G
authors: KG
authors: Schuurman
authors: Miriam E
authors: ME
authors: van Strien
authors: Jeroen
authors: J
authors: Melief
authors: Debbie
authors: D
authors: Hendrickx
authors: Elly M
authors: EM
authors: Hol
authors: Corbert
authors: C
authors: van Eden
authors: Sabina
authors: S
authors: Luchetti
authors: Inge
authors: I
authors: Huitinga
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001254:Astrocytoma / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D015331:Cohort Studies; D003337:Corpus Callosum / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology; D009426:Netherlands; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger; D018167:Receptors, Calcitriol / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D014807:Vitamin D / Q000494:pharmacology; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D005904:Glial Fibrillary Acidic Protein; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D014409:Tumor Necrosis Factor-alpha; D014807:Vitamin D; D007371:Interferon-gamma; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase