Signal transduction pathways in oligodendrocytes: Role of tumor necrosis factor-α

Abstract

We have used a combination of electrophysiological and biochemical approaches to investigate the effects and the mechanisms of action of tumor necrosis factor-α (TNF-α) on cultured oligodendrocytes (OLGs). Our studies have led to the following conclusions: (1) prolonged exposure of mature ovine OLGs to TNF-α leads to inhibition of process extension, membrane depolarization and a decrease in the amplitudes of both inwardly rectifying and outward K+ currents; (2) brief exposure of OLGs to TNF-α does not elicit membrane depolarization or consistent changes in cytosolic Ca2+ levels; (3) incubation of OLGs with TNF-α for 1 hr results in inhibition of phosphorylation of myelin basic protein and 2′, 3′-cyclic nucleotide phosphohydrolase. Ceramides, which have been shown to be effectors of TNF-α, are ineffective in inhibiting phosphorylation, whereas sphingomyelinase mimicks TNF-α in this action. These observations suggest that other products of sphingomyelin hydrolysis may be the mediator(s) of TNF-α effect on protein phosphorylation. We have thus demonstrated that TNF-α can perturb the functions of OLGs via modulation of ion channels and of protein phosphorylation without necessarily inducing cell death. It is conceivable that modulation of ion channels and protein phosphorylation constitutes effective mechanisms for the participation of cytokines in signal transduction during myelination, demyelination and remyelination.