title: Insulin-like growth factor I protects oligodendrocytes from tumor necrosis factor-alpha-induced injury.
abstract: 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-1beta 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.
authors.affiliation: Department of Pediatrics, The University of North Carolina at Chapel Hill, 27599-7220, USA.
authors.forename: P
authors.initials: P
authors.lastname: Ye
authors.forename: A J
authors.initials: AJ
authors.lastname: D'Ercole
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D004676:Myelin Basic Protein / Q000235:genetics; D018991:Myelin Proteolipid Protein / Q000235:genetics; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D015853:Cysteine Proteinase Inhibitors; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C103192:butyloxycarbonyl-O-methyl-aspartyl-fluoromethyl ketone; D007334:Insulin-Like Growth Factor I