Redox regulation of cytokine-mediated inhibition of myelin gene expression in human primary oligodendrocytes

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disorder of the central nervous system (CNS) of unknown etiology. Several studies have shown that demyelination in MS is caused by proinflammatory mediators which are released by perivascular infiltrates and/or activated glial cells. To understand if proinflammatory mediators such as IL (interleukin)-1β and TNF (tumor necrosis factor)-α are capable of modulating the expression of myelin-specific genes, we investigated the effect of these cytokines 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. Interestingly, both IL-1β and TNF-α markedly inhibited the expression of MOG, CNPase, and PLP but not MBP, the effect that was blocked by antioxidants such as N-acetylcysteine (NAC) and pyrrolidine dithiocarbamate (PDTC). Consistently, oxidants and prooxidants like H2O2 and diamide also markedly inhibited the expression of MOG, CNPase, and PLP. Furthermore, both IL-1β and TNF-α induced the production of H2O2. Taken together, these studies suggest that proinflammatory cytokines inhibit the expression of myelin genes in human primary oligodendrocytes through the alteration of cellular redox.