Maturation of oligodendrocytes is more sensitive to TNF alpha than is survival of precursors and immature oligodendrocytes.

TNF alpha is a cytokine recently found at high levels in multiple sclerosis plaques. The present study addressed the questions whether TNF alpha might affect oligodendrocytes at various stages of maturation and whether the effects of transient incubation with TNF alpha would last during subsequent differentiation. Primary glial-cell cultures were treated with 1000 U/ml of TNF alpha for 48 h, beginning on days 1, 2, 6, 8 and 10 days in vitro, and allowed to grow for up to 3 weeks (total) in vitro. A significant deficit of O4+/MBP+ cells in the TNF alpha-treated cultures became obvious during the second week. Moreover, the morphology of the O4-positive cells became more complex with time in the control cultures, whereas fewer cells in TNF alpha-treated cultures developed into cells with sheets of membrane or > four processes. In TNF alpha-treated cultures, the numbers of O4-positive cells increased by about four-fold during weeks 2 and 3, but the numbers of MBP-positive cells did not and were significantly lower than the numbers of MBP-positive cells in control cultures. The effects of TNF alpha were apparent 1 to 14 days after treatment, suggesting long-term influences, and could be initiated at diverse stages of maturation. Future testing of hypothetical mechanisms by which TNF alpha may inhibit oligodendrocyte differentiation should impact on our understanding of the apparent limitations on remyelination in the mature CNS.