Premium
IGF‐1 protects oligodendrocyte progenitors against TNFα‐induced damage by activation of PI3K/Akt and interruption of the mitochondrial apoptotic pathway
Author(s) -
Pang Yi,
Zheng Baoying,
Fan LirWan,
Rhodes Philip G.,
Cai Zhengwei
Publication year - 2007
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.20530
Subject(s) - protein kinase b , pi3k/akt/mtor pathway , mapk/erk pathway , biology , microbiology and biotechnology , wortmannin , programmed cell death , cancer research , proinflammatory cytokine , kinase , apoptosis , signal transduction , immunology , inflammation , biochemistry
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‐α (TNFα)‐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 TNFα resulted in death of OPCs. IGF‐1 protected OPCs from TNFα 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 PD98059, the MAPK kinase/ERK kinase inhibitor. The downstream events of IGF‐1‐triggered survival signals included phosphorylation of BAD, blockade of TNFα‐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. © 2007 Wiley‐Liss, Inc.