IGF-1 protects oligodendrocyte progenitors against TNFalpha-induced damage by activation of PI3K/Akt and interruption of the mitochondrial apoptotic pathway.
Proinflammatory cytokine-mediated injury to oligodendrocyte progenitor cells (OPCs) has been proposed as a cause of periventricular leukomalacia (PVL), the most common brain injury found in preterm infants. Preventing death of OPCs is a potential strategy to prevent or treat PVL. In the current study, we utilized an in vitro cell culture system to investigate the effect of insulin-like growth factor-1 (IGF-1) on tumor necrosis factor-alpha (TNFalpha)-induced OPC injury and the possible mechanisms involved. OPCs were isolated from neonatal rat optic nerves and cultured in chemically defined medium (CDM) supplemented with platelet-derived growth factor and basic fibroblast growth factor. Exposure to TNFalpha resulted in death of OPCs. IGF-1 protected OPCs from TNFalpha cytotoxicity in a dose-dependent manner as measured by the XTT and TUNEL assays. IGF-1 activates both the PI3K/Akt and the extracellular signal-regulated kinase (ERK) pathway. However, IGF-1-enhanced cell survival signals were mediated by the PI3K/Akt, but not by the ERK pathway, as evidenced by the observation that IGF-1-enhanced cell survival was partially abrogated by Akti, the Akt inhibitor, or wortmannin, the PI3K inhibitor, but not by PD98,059, the MAPK kinase/ERK kinase inhibitor. The downstream events of IGF-1-triggered survival signals included phosphorylation of BAD, blockade of TNFalpha-induced translocation of Bax from the cytosol to the mitochondrial membrane, and suppression of caspase-9 and caspase-3 activation. These observations indicate that the protection of OPCs by IGF-1 is mediated, at least partially, by interruption of the mitochondrial apoptotic pathway via activation of PI3K/Akt.
Pang
Yi
Y
Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
Zheng
Baoying
B
Fan
Lir-Wan
LW
Rhodes
Philip G
PG
Cai
Zhengwei
Z
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009836:Oligodendroglia / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013234:Stem Cells / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000502:physiology
D014409:Tumor Necrosis Factor-alpha; D051025:bcl-Associated Death Protein; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020169:Caspases