Insulin-like growth factor I protects oligodendrocytes from tumor necrosisfactor-alpha-induced injury

Tumor necrosis factor-alpha TNF-alpha has been causally implicated in sever al demyelinating disorders, including multiple sclerosis. Because insulin-l ike growth factor I(IGF-I) is a potent stimulator of myelination, we invest igated whether it can protect oligodendrocytes and myelination from TNF-alp ha-induced damage using mouse glial cultures as a model. Compared with cont rols, TNF-alpha decreased oligodendrocyte number by approximately 40% and d oubled the number of apoptotic oligodendrocytes and their precursors. Addit ion of Bocaspartyl(Ome)-fluoromethyl ketone (BAF), an inhibitor of interleu kin-lp converting enzyme (ICE)/caspase proteases, blocked TNF-alpha-induced reductions in oligodendrocytes, indicating that the TNF-alpha-induced redu ction in oligodendrocytes is, at least in part, due to apoptosis, and that ICE/caspases are one of TNF-alpha action mediators. Simultaneous addition o f IGF-I to TNF-alpha-treated cultures negated these TNF-alpha effects nearl y completely. Furthermore, IGF-I promoted oligodendrocyte precursor prolife ration and/or differentiation in TNF-alpha-treated cultures. To analyze TNF -alpha and IGF-I actions on oligodendrocyte function, we measured the abund ance of messenger RNAs (mRNAs) for two major myelin-specific proteins, myel in basic protein (MBP) and proteolipid protein (PLP). While TNF-alpha decre ased 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 th at TNF-alpha can mediate oligodendrocyte and myelin damage, and indicate th at IGF-I protects oligodendrocytes from TNF-alpha insults by blocking TNF-a lpha-induced apoptosis, and by promoting oligodendrocyte and precursor prol iferation/differentiation and myelin protein gene expression.