Japanese encephalitis virus down-regulates thioredoxin and induces ROS-mediated ASK1-ERK/p38 MAPK activation in human promonocyte cells.
Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, causes severe neurological disease with high mortality. Molecular mechanisms of JEV pathogenesis such as upstream apoptotic processes and pathways are not yet completely resolved or understood. In this study, JEV replication in human promonocyte cells induced time-dependent apoptosis and activated virus dose-dependent caspases 3, 8 and 9. Proteomic analysis demonstrated up- and down-regulated (more or less than 1.5-fold) proteins in JEV-infected promonocyte cells. Biological process categorization showed processes of antioxidation, free radical removal, and sulfur redox metabolism entailed many identified up- and down-regulated proteins. Down-regulation of thioredoxin, confirmed by using Western blotting, was involved in the apoptosis process of the oxidative stress response pathway. JEV infection caused increased intracellular ROS production and activation of ASK1-ERK/p38 MAPK signaling. ERK/p38 MAPK inhibitor PD98059 treatment definitely suppressed this apoptosis. Down-regulation of thioredoxin, increased intracellular ROS, and activation of ASK1-ERK/p38 MAPK signaling all were associated with JEV-induced apoptosis. These results are suggestive of an oxidative stress-pathway as a key element of JE pathogenesis.
Yang
Tsuey-Ching
TC
Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan.
Lai
Chien-Chen
CC
Shiu
Su-Lian
SL
Chuang
Pei-Hsin
PH
Tzou
Bo-Cheng
BC
Lin
Ying-Ya
YY
Tsai
Fuu-Jen
FJ
Lin
Cheng-Wen
CW
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000096:biosynthesis; D053181:Caspase 8 / Q000096:biosynthesis; D053453:Caspase 9 / Q000096:biosynthesis; D002460:Cell Line; D002522:Chlorocebus aethiops; D004668:Encephalitis Viruses / Q000472:pathogenicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000096:biosynthesis*; D055017:Monocyte-Macrophage Precursor Cells / Q000821:virology*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013879:Thioredoxins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D017382:Reactive Oxygen Species; C491203:TXN protein, human; D013879:Thioredoxins; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one