Journal
VIRUS RESEARCH
Volume 197, Issue -, Pages 75-84Publisher
ELSEVIER
DOI: 10.1016/j.virusres.2014.12.016
Keywords
Enterovirus 71; Cytokine; MAPK; ERK; JNK; NF-kappa B
Categories
Funding
- State Key Laboratory of Pharmaceutical Biotechnology of Nanjing University [KFGW-200902]
- Rapid Agricultural Response Fund (RARF) from Minnesota MAES
- Natural Science Foundation of Jiangsu Province [BK20141078]
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Enterovirus 71 (EV71) has become an important neurotropic enterovirus in children since the eradication of the poliovirus. A cytokine storm with elevated levels of proinflammatory cytokines is proposed as critical to the pathogenesis of EV71-induced brain stem encephalitis with pulmonary edema, often a fatal complication. Mitogen-activated protein kinases (MAPK) are involved in cellular processes including immune responses and apoptosis. EV71 infection can trigger MAPK activation in human cells, and extracellular signal-regulated kinase (ERK) signaling is essential for EV71 replication. In this study, we report that in EV71-infected human intestinal epithelial cells (HT-29), both ERK1/2 and Jun-N-terminal kinase 1/2 (JNK1/2) were phosphorylated and activated. While MAPK was not involved in the induction of IL-1 beta, the expressions of IL-6 and IL-8 were positively regulated by both ERK1/2 and JNK1/2, which were also responsible for type I IFN induction. HT-29 cells underwent apoptosis in EV71 infection, but the activation of ERK1/2 and JNK1/2 signaling appeared to suppress induction of TNF-alpha and FasL and inhibit extrinsic apoptosis in infected cells. Activation of NF-kappa B was also observed in HT-29 cells in EV71 infection, leading to increased viral replication and proinflammatory cytokine induction. However, the activation of NF-kappa B was inhibited by the inhibitors of ERK1/2, p38 and JNK1/2, indicating that a cross-talk may exist between MAPK and NF-kappa B pathways in EV71-infected intestinal epithelial cells. Understanding host responses and their underlying mechanisms may help develop effective therapeutics against EV71 and tools for control of future EV71 outbreaks. (C) 2014 Elsevier B.V. All rights reserved.
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