title: Down-regulation of Myelin Gene Expression in Human Oligodendrocytes by Nitric Oxide: Implications for Demyelination in Multiple Sclerosis.
abstract: Multiple sclerosis (MS) is a chronic autoimmune demyelinating disorder of the central nervous system (CNS) with unknown etiology. Several studies have shown that demyelination in MS is caused by proinflammatory mediators and nitric oxide (NO), which is released by perivascular infiltrates and/or activated glial cells. Both endogenous NO released by microglia and astrocytes; and NO generated from exogenous NO donors are known to induce oligodendrocytes death. However, the molecular mechanism of oligodendroglial death is poorly understood. Here we explore the role of NO in modulating the expression of myelin-specific genes that leads to oligodendroglial death. We investigated the effect of NO on the expression of myelin basic protein (MBP), 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), myelin oligodendrocyte glycoprotein (MOG), and proteolipid protein (PLP) in human primary oligodendrocytes. Combination of IFN-γ and bacterial lipopolysaccharide (LPS) or double stranded RNA in the form of polyIC induced the production of NO and decreased the expression of myelin gene in human fetal mixed glial cultures. Either a scavenger of NO (PTIO) or an inhibitor of inducible nitric oxide synthase (L-NIL) abrogated (LPS+IFN-γ)- and polyIC-mediated suppression of myelin genes in human mixed glial cells. The role of NO was further corroborated by the inhibition of myelin gene expression in purified human oligodendroglia by several NO donors including SNP, NOC-7, SIN-1, and SNAP. This study illustrates a novel biological role of NO in down-regulating the expression of myelin genes preceding the death of oligodendrocytes.
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Malabendu
authors.initials: M
authors.lastname: Jana
authors.forename: Kalipada
authors.initials: K
authors.lastname: Pahan
keywords: IFN-γ; LPS; Myelin gene expression; Nitric oxide; Oligodendrocytes; polyIC