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Stat3 mediates LIF‐induced protection of astrocytes against toxic ROS by upregulating the UPC2 mRNA pool
Author(s) -
Lapp Daniel W.,
Zhang Samuel S.,
Barnstable Colin J.
Publication year - 2014
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.22594
Subject(s) - reactive oxygen species , biology , mitochondrial ros , leukemia inhibitory factor , astrocyte , microbiology and biotechnology , apoptosis , oxidative stress , programmed cell death , mitochondrion , downregulation and upregulation , stat3 , intracellular , signal transduction , biochemistry , immunology , endocrinology , central nervous system , inflammation , gene , interleukin 6
Reactive oxygen species (ROS) have been implicated in various types of CNS damage, including stroke. We used a cultured astrocyte model to explore mechanisms of survival of CNS cells following ROS damage. We found that pretreatment with leukemia inhibitory factor (LIF) preserves astrocytes exposed to toxic levels of t ‐BHP by inhibiting an increase in intracellular ROS following t ‐BHP treatment. Astrocytes lacking functional Stat3 did not benefit from the pro‐survival or antioxidant effects of LIF. Inhibition of mitochondrial uncoupling protein 2 (UCP2) using a chemical inhibitor or siRNA abrogates the prosurvival effects of LIF, indicating a critical role for UCP2 in modulation of mitochondrial ROS production in survival following ROS exposure. LIF treatment of astrocytes results in increased UCP2 mRNA that is accompanied by an increase in Stat3 binding to the UCP2 promoter region. Although treatment with LIF alone did not increase UCP2 protein, a combination of LIF treatment and ROS stress led to increased UCP2 protein levels. We conclude that LIF protects astrocytes from ROS‐induced death by increasing UCP2 mRNA, allowing cells to respond to ROS stress by rapidly producing UCP2 protein that ultimately decreases endogenous mitochondrial ROS production. GLIA 2014;62:159–170