EV71 induces COX‐2 expression via c‐Src/PDGFR/PI3K/Akt/p42/p44 MAPK/AP‐1 and NF‐κB in rat brain astrocytes

Tung, Wei Hsuan; Lee, I-Te; Hsieh, Hsi‐Lung; Yang, Che‐Hua

doi:10.1002/jcp.22133

Cited by 58 publications

(41 citation statements)

References 27 publications

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“…In rat vascular smooth muscle cells, EV71 stimulates NF-kB-regulated luciferase activity in a timedependent manner, and such activity reaches a peak at 0.5 h postinfection (39). Exposure of SK-N-SH cells to EV71 can stimulate translocation of NF-kB (p65) into nucleus and degradation of IkBa at 1 h postinfection (40,41). It should be noted that in those studies, NF-kB was activated at the early stage (within 1 h) FIGURE 6.…”

Section: Discussionmentioning

confidence: 99%

Enterovirus 71 2C Protein Inhibits TNF-α–Mediated Activation of NF-κB by Suppressing IκB Kinase β Phosphorylation

Zheng

Zhang

et al. 2011

The Journal of Immunology

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Enterovirus 71 (EV71), a single, positive-stranded RNA virus, has been regarded as the most important neurotropic enterovirus after the eradication of the poliovirus. EV71 infection can cause hand, foot, and mouth disease or herpangina. Cytokine storm with elevated levels of proinflammatory and inflammatory cytokines, including TNF-α, has been proposed to explain the pathogenesis of EV71-induced disease. TNF-α–mediated NF-κB signaling pathway plays a key role in inflammatory response. We hypothesized that EV71 might also moderate host inflammation by interfering with this pathway. In this study, we tested this hypothesis and identified EV71 2C protein as an antagonist of TNF-α–mediated activation of NF-κB signaling pathway. Expression of 2C protein significantly reduced TNF-α–mediated NF-κB activation in 293T cells as measured by gene reporter and gel mobility shift assays. Furthermore, overexpression of TNFR-associated factor 2-, MEK kinase 1-, IκB kinase (IKK)α-, or IKKβ-induced NF-κB activation, but not constitutively active mutant of IKKβ (IKKβ SS/EE)-induced NF-κB activation, was inhibited by 2C protein. These data together suggested that the activation of IKKβ is most likely targeted by 2C; this notion was further strengthened by immunoblot detection of IKKβ phosphorylation and IκBα phosphorylation and degradation. Coimmunoprecipitation and colocalization of 2C and IKKβ expressed in mammalian cells provided compelling evidence that 2C interacts with IKKβ. Collectively, our data indicate that EV71 2C protein inhibits IKKβ activation and thus blocks NF-κB activation.

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Section: Discussionmentioning

confidence: 99%

Enterovirus 71 2C Protein Inhibits TNF-α–Mediated Activation of NF-κB by Suppressing IκB Kinase β Phosphorylation

Zheng

Zhang

et al. 2011

The Journal of Immunology

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“…6d, thrombin markedly stimulated p42/p44 MAPK phosphorylation in a time-dependent manner, which was attenuated by pretreatment with U0126. c-Src, tyrosine kinase receptors, and PI3K/Akt have been shown to be involved in p42/p44 MAPK activation [30]. Therefore, we investigated the roles of proteolytic activity of thrombin, PAR-1, Gi protein, c-Src, Pyk2, and EGFR on p42/ p44 MAPK phosphorylation stimulated by thrombin, as shown in Fig.…”

Section: Thrombin Induces Mmp-9 Expression Via Pi3k/akt Signaling Patmentioning

confidence: 99%

Thrombin Enhanced Matrix Metalloproteinase-9 Expression and Migration of SK-N-SH Cells via PAR-1, c-Src, PYK2, EGFR, Erk1/2 and AP-1

2016

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Neuroinflammation is a hallmark of neurodegenerative disorders in the central nerve system (CNS). Thrombin has been known as one of the factors in pathological processes including migration, blood-brain barrier breakdown, brain edema formation, neuroinflammation, and neuronal death. Thrombin has been shown to be a regulator of matrix metalloproteinase (MMPs) expression leading to cell migration. Among MMPs, the elevated expression of MMP-9 has been observed in patients with brain diseases, which may contribute to the pathology of neuroinflammatory and neurodegenerative diseases. However, the mechanisms underlying thrombin-induced MMP-9 expression in SK-N-SH cells were not completely understood. Here, we used gelatin zymography, Western blot, real-time PCR, promoter activity assay, and cell migration assay to demonstrate that thrombin induced the expression of pro-form MMP-9 protein and messenger RNA (mRNA), and promoter activity in SK-N-SH cells, which were attenuated by pretreatment with the pharmacological inhibitor of protease-activated receptor-1 (PAR-1, SCH79797), Gi-coupled receptor (GPA2), c-Src (PP1), Pyk2 (PF431396), EGFR (AG1478), PI3K (LY294002), Akt (SH-5), MEK1/2 (U0126), or AP-1 (TanshinoneIIA) and transfection with small interfering RNA (siRNA) of PAR-1, Gi, c-Src, Pyk2, EGFR, Akt, p44, p42, or c-Jun. Moreover, thrombin-stimulated c-Src, Pyk2, EGFR, Akt, p42/p44 MAPK, or c-Jun phosphorylation was attenuated by their respective inhibitor of PP1, PF431396, AG1478, SH-5, U0126, or TanshinoneIIA. Finally, pretreatment with these inhibitors also blocked thrombin-induced SK-N-SH cell migration. Our results concluded that thrombin binding to PAR-1 receptor activated Gi-protein/c-Src/Pyk2/EGFR/PI3K/Akt/p42/p44 MAPK cascade, which in turn elicited AP-1 activation and ultimately evoked MMP-9 expression and cell migration in SK-N-SH cells.

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“…EV71 has been proposed to reach the CNS via retrograde axonal transport, whereby the virus actively replicates in skeletal muscles, infects motor neurons at the neuro-muscular junctions and enters the CNS to eventually accumulate in the brainstem3181920. In vitro , EV71 neurovirulence has been studied in several neuronal cell lines including SK-N-SH (neuroblastoma)21, SH-SY5Y (neuroblastoma)22, SF268 (glioblastoma)23, RBA-1 (astrocyte)24, and U251 (astrocyte)25. However, as neuronal cells isolated from different tissues display different features and characteristics, it is possible that data obtained with these cell lines may not reflect accurately the events occurring at the neuromuscular junctions during infection.…”

mentioning

confidence: 99%

Enterovirus 71 infection of motor neuron-like NSC-34 cells undergoes a non-lytic exit pathway

Too

Yeo

Sessions

et al. 2016

Sci Rep

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Enterovirus 71 (EV71) causing Hand, Foot and Mouth Disease, is regarded as the most important neurotropic virus worldwide. EV71 is believed to replicate in muscles and infect motor neurons to reach the central nervous system (CNS). To further investigate the mechanisms involved, we have employed the motor neuron cell line NSC-34. NSC-34 cells were permissive to EV71 and virus production yields were strain-dependent with differential efficacy at the entry, replication and egress steps. Furthermore, unlike all the other cell lines previously reported, EV71-infected NSC-34 cells neither displayed cytopathic effect nor underwent apoptosis. Instead, autophagy was markedly up-regulated and virus-containing autophagic vacuoles were isolated from the culture supernatant, providing the first experimental evidence that EV71 can adopt a non-lytic exit pathway. Finally, the ability of EV71 to infect productively NSC-34 cells correlated with its ability to invade the CNS in vivo, supporting the relevance of NSC-34 cells to study the intrinsic neurovirulence of EV71 strains.

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EV71 induces COX‐2 expression via c‐Src/PDGFR/PI3K/Akt/p42/p44 MAPK/AP‐1 and NF‐κB in rat brain astrocytes

Cited by 58 publications

References 27 publications

Enterovirus 71 2C Protein Inhibits TNF-α–Mediated Activation of NF-κB by Suppressing IκB Kinase β Phosphorylation

Enterovirus 71 2C Protein Inhibits TNF-α–Mediated Activation of NF-κB by Suppressing IκB Kinase β Phosphorylation

Thrombin Enhanced Matrix Metalloproteinase-9 Expression and Migration of SK-N-SH Cells via PAR-1, c-Src, PYK2, EGFR, Erk1/2 and AP-1

Enterovirus 71 infection of motor neuron-like NSC-34 cells undergoes a non-lytic exit pathway

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