title: Intrinsic apoptosis and proinflammatory cytokines regulated in human astrocytes infected with enterovirus 71.
abstract: Enterovirus 71 (EV71) has emerged as a clinically important neurotropic virus following poliovirus eradication. However, the mechanism of EV71-induced neurological manifestation remains largely unclear. In this study, we showed that human astrocytes were susceptible to EV71 and viral RNA was first detected at 12 h post-infection (p.i.), whilst viral proteins were detected at 36 h p.i. EV71-infected astrocytes underwent apoptosis, in which cytochrome c was released from mitochondria to the cytosol and caspase-9 was activated. Interestingly, caspase-2 and -8 were not cleaved or activated during the infection, whilst a selective inhibitor of caspase-9, Z-LEHD-FMK, blocked the cleavage of caspase-3 and -7, indicating that only the mitochondria-mediated intrinsic apoptotic pathway was activated in EV71-infected astrocytes. EV71 infection also induced proinflammatory cytokines, including IL-6, IL-8, CCL5 and IFN-γ-inducible protein (IP)-10 in astrocytes, which may play a critical role in EV71-induced neuroinflammation and neurological complications. By using inhibitors of mitogen-activated protein kinases (MAPKs), we demonstrated that the induction of the cytokines was mainly regulated by the MAPK p38 signalling pathway as a significant reduction of the cytokines was observed when treated with p38 inhibitors. This study demonstrated that human astrocytes were susceptible to EV71, and the infection led to intrinsic apoptosis and induction of p38-regulated proinflammatory cytokines. These findings further our understanding of the neuropathogenesis in severe cases of EV71 infection.
authors: The State Key Laboratory of Pharmaceutical Biotechnology and Medical School, Jiangsu Provincial Key Laboratory of Medicine, Nanjing University, Nanjing, PR China.|Nanjing Children's Hospital, Nanjing, PR China.
authors: Chunyang
authors: C
authors: Wang
authors: The State Key Laboratory of Pharmaceutical Biotechnology and Medical School, Jiangsu Provincial Key Laboratory of Medicine, Nanjing University, Nanjing, PR China.|Nanjing Children's Hospital, Nanjing, PR China.
authors: Renmen
authors: R
authors: Zhou
authors: The State Key Laboratory of Pharmaceutical Biotechnology and Medical School, Jiangsu Provincial Key Laboratory of Medicine, Nanjing University, Nanjing, PR China.
authors: Zerui
authors: Z
authors: Zhang
authors: The State Key Laboratory of Pharmaceutical Biotechnology and Medical School, Jiangsu Provincial Key Laboratory of Medicine, Nanjing University, Nanjing, PR China.|Nanjing Children's Hospital, Nanjing, PR China.
authors: Yu
authors: Y
authors: Jin
authors: College of Veterinary Medicine, University of Minnesota at Twin Cities, Saint Paul, MN 55108, USA.
authors: Carol J
authors: CJ
authors: Cardona
authors: College of Veterinary Medicine, University of Minnesota at Twin Cities, Saint Paul, MN 55108, USA.|The State Key Laboratory of Pharmaceutical Biotechnology and Medical School, Jiangsu Provincial Key Laboratory of Medicine, Nanjing University, Nanjing, PR China.
authors: Zheng
authors: Z
authors: Xing
mesh_terms: D017209:Apoptosis; D001253:Astrocytes / Q000276:immunology* / Q000821:virology*; D053453:Caspase 9 / Q000032:analysis; D002478:Cells, Cultured; D045304:Cytochromes c / Q000032:analysis; D016207:Cytokines / Q000096:biosynthesis*; D003593:Cytoplasm / Q000737:chemistry; D029821:Enterovirus A, Human / Q000254:growth & development* / Q000276:immunology*; D006801:Humans; D020935:MAP Kinase Signaling System
chemical_list: D016207:Cytokines; D045304:Cytochromes c; D053453:Caspase 9