Insulin-like growth factor-I ameliorates demyelination induced by tumor necrosis factor-alpha in transgenic mice.
Our groups have reported that tumor necrosis factor-alpha (TNF-alpha) causes myelin damage and apoptosis of oligodendrocytes and their precursors in vitro and in vivo. We also have reported that insulin-like growth factor-I (IGF-I) can protect cultured oligodendrocytes and their precursors from TNF-alpha-induced damage. In this study, we investigated whether IGF-I can protect oligodendrocytes and myelination from TNF-alpha-induced damage in vivo by cross-breeding TNF-alpha transgenic (Tg) mice with IGF-I Tg mice that overexpress IGF-I exclusively in brain. At 8 weeks of age, compared with those of wild-type (WT) mice, the brain weights of TNF-alpha Tg mice were decreased by approximately 20%, and those of IGF-I Tg mice were increased by approximately 20%. The brain weights of mice that carry both TNF-alpha and IGF-I transgenes (TNF-alpha/IGF-I Tg mice) did not differ from those of WT mice. As judged by histochemical staining and immunostaining, myelin content in the cerebellum of TNF-alpha/IGF-I Tg mice was similar to that in WT mice and much more than that in TNF-alpha Tg mice. Consistently, Western immunoblot analysis showed that myelin basic protein (MBP) abundance in the cerebellum of TNF-alpha/IGF-I Tg mice was double that in TNF-alpha Tg mice. In comparison with WT mice, the number of oligodendrocytes was decreased by approximately 36% in TNF-alpha Tg mice, whereas it was increased in IGF-I Tg mice by approximately 40%. Oligodendrocyte number in TNF-alpha/IGF-I Tg mice was almost twice that in TNF-alpha Tg mice. Furthermore, IGF-I overexpression significantly reduced TNF-alpha-induced increases in apoptotic cell number, active caspase-3 abundance, and degradaion of MBP. Our results indicate that IGF-I is capable of protecting myelin and oligodendrocytes from TNF-alpha-induced damage in vivo.
Ye
Ping
P
Division of Endocrinology, Department of Pediatrics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7039, USA. ping_ye@med.unc.edu
Kollias
George
G
D'Ercole
A Joseph
AJ
D000818:Animals; D000941:Antigens / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling / Q000379:methods; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000378:metabolism; D009929:Organ Size / Q000235:genetics; D011509:Proteoglycans / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014409:Tumor Necrosis Factor-alpha; D000099216:Chondroitin Sulfate Proteoglycan 4
D000941:Antigens; D053148:Caspase 3; D051549:Glutathione S-Transferase pi; D007334:Insulin-Like Growth Factor I; D004676:Myelin Basic Protein; D011509:Proteoglycans; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000099216:Chondroitin Sulfate Proteoglycan 4