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Tumor necrosis factor-[alpha] (TNF-[alpha]) has been causally implicated in several demyelinating disorders, including multiple sclerosis. Because insulin-like growth factor I (IGF-I) is a potent stimulator of myelination, we investigated whether it can protect oligodendrocytes and myelination from TNF-[alpha]-induced damage using mouse glial cultures as a model. Compared with controls, TNF-[alpha] decreased oligodendrocyte number by approximately 40% and doubled the number of apoptotic oligodendrocytes and their precursors. Addition of Boc-aspartyl(Ome)-fluoromethyl ketone (BAF), an inhibitor of interleukin-1[beta] converting enzyme (ICE)/caspase proteases, blocked TNF-[alpha]-induced reductions in oligodendrocytes, indicating that the TNF-[alpha]-induced reduction in oligodendrocytes is, at least in part, due to apoptosis, and that ICE/caspases are one of TNF-[alpha] action mediators. Simultaneous addition of IGF-I to TNF-[alpha]-treated cultures negated these TNF-[alpha] effects nearly completely. Furthermore, IGF-I promoted oligodendrocyte precursor proliferation and/or differentiation in TNF-[alpha]-treated cultures. To analyze TNF-[alpha] and IGF-I actions on oligodendrocyte function, we measured the abundance of messenger RNAs (mRNAs) for two major myelin-specific proteins, myelin basic protein (MBP) and proteolipid protein (PLP). While TNF-[alpha] decreased MBP and PLP mRNA abundance by 5- to 6-fold, IGF-I abrogated TNF-[alpha]-induced reductions in a dose- and time-dependent manner. The changes in MBP and PLP mRNA abundance could not be completely explained by the changes in oligodendrocyte number, indicating that myelin protein gene expression is regulated by both TNF-[alpha] and IGF-I. These data support the hypothesis that TNF-[alpha] can mediate oligodendrocyte and myelin damage, and indicate that IGF-I protects oligodendrocytes from TNF-[alpha] insults by blocking TNF-[alpha]-induced apoptosis, and by promoting oligodendrocyte and precursor proliferation/differentiation and myelin protein gene expression.

Copyright (C) 1999 by The Endocrine Society