Hydrogen peroxide enhances TRAIL-induced cell death through up-regulation of DR5 in human astrocytic cells.
The central nervous system (CNS) is particularly vulnerable to reactive oxygen species (ROS), which have been implicated in the pathogenesis of various neurological disorders. The TNF superfamily of cytokines, especially tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), induces caspase-dependent cell death and is also implicated in various neurodegenerative diseases. In this study, we investigated the relationship between ROS and TRAIL-induced cell death. Exposure to hydrogen peroxide (H(2)O(2)) (100 microM) sensitized human astrocytic cells to TRAIL-induced cell death (up to 7-fold induction). To delineate the molecular mechanisms responsible for H(2)O(2)-induced sensitization, we examined expression of various genes (Caspase-8, Fas, FasL, DR4, DR5, DcR1, DcR2, TRAIL, TNFRp55) related to TRAIL-induced cell death. Treatment with H(2)O(2) significantly increased DR5 mRNA and protein expression in a time- and dose-dependent manner. H(2)O(2)-mediated cell death was blocked upon treatment with DR5:Fc protein, a TRAIL-specific antagonistic protein. These findings collectively suggest that oxidative stress sensitizes human astroglial cells to TRAIL-induced cell death through up-regulation of DR5 expression.
Medical Research Center for Environmental Toxico-Genomics and Proteomics, Korea University College of Medicine, Anam dong-5ga 126-1, Seongbuk-gu, Seoul 136-705, Republic of Korea. dkwon@korea.ac.kr
Daeho
D
Kwon
Kyungsun
K
Choi
Chulhee
C
Choi
Etty N
EN
Benveniste
D017209:Apoptosis / Q000235:genetics; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000633:toxicity; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015854:Up-Regulation
D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D006861:Hydrogen Peroxide