Expression of Vitamin D Receptor and Metabolizing Enzymes in Multiple Sclerosis—Affected Brain Tissue

• DOI: 10.1097/nen.0b013e31827f4fcc
• Publication Date: 2013-01-18T08:12:40Z
• Authors: Joost Smolders; Karianne G. Schuu...; Miriam E. van Strien; Jeroen Melief; Debbie Hendrickx; Elly M. Hol; Corbert van Eden; Sabina Luchetti; Inge Huitinga
• Keywords: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Adult; Aged, 80 and over; Male; Multiple Sclerosis; Brain; Astrocytoma; Middle Aged; Kidney; Corpus Callosum; Cohort Studies; Interferon-gamma; 03 medical and health sciences; 0302 clinical medicine; Gene Expression Regulation; Liver; Astrocytes; Glial Fibrillary Acidic Protein; Humans; Female; Cells, Cultured; Aged

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.