Characterization of the multiple sclerosis traits: Nuclear receptors (NR) impaired apoptosis pathway and the role of 1-alpha 25-dihydroxyvitamin D3

Low expression of NR4A gene family members (NR4A1, NR4A3) and 1-alpha, 25-dihydroxyvitamin D-3 receptor (VDR) genes was demonstrated in peripheral blood mononuclear cells (PBMC) of subjects evaluated during the pre-disease state of multiple sclerosis (MS-to-be, MS2b), in patients with clinically isolated syndrome (CIS) during the very early presentation of neurological symptomatology and in relapsing-remitting MS (RRMS) patients. Both NR4A1 and NR4A3 are known to be involved in T-cell receptor-induced apoptosis and are regulated by VDR. We further evaluated the precise implications of apoptosis signaling regulators in relation to MS pathogenesis at the cellular level by studying the effects of 1-alpha, 25-dihydroxyvitamin D-3 (Vit D-3) upon NR4A1 expression. We demonstrated that the low apoptotic level in MS patients was repaired by Vit D-3 mainly through NR4A1 and to a lesser extent thorough BCL2-associated X protein (BAX). These findings prove a role for Vit D-3 as a possible therapeutic intervention in MS patients aimed to activate the repressed apoptosis and enhance better control of the disease. (C) 2011 Elsevier B.V. All rights reserved.