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

Wei Hsuan Tung, I-Ta Lee, Hsi Lung Hsieh, Chuen Mao Yang

Research output: Contribution to journalArticle

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Abstract

Enterovirus 71 (EV71) induces the expression of cyclooxgenase (COX)-2 served as a major neurotoxic factor inCNSinjury. However, the mechanisms underlying EV71-initiated intracellular signaling pathways leading to COX-2 expression remain unknown. Therefore, we investigated the mechanisms underlying EV71-induced COX-2 expression and prostaglandin E2 (PGE2) production in rat brain astrocytes (RBA)-1, determined by Western blotting, RT-PCR, and promoter assay. Here, we reported that EV71-indued COX-2 expression and PGE2 production were attenuated by pretreatment with the inhibitors of c-Src (PP1), PDGFR (AG1296), PI3K (Wortmannin), MEK1/2 (PD98059), NF-kB (helenalin), and AP-1 (Tanshinone) and transfection with shRNA or siRNA of c-Src, PDGFR, p85, c-Jun, c-Fos, ERK1, or ERK2. We further observed that EV71-induced activation of Akt and p42/p44 MAPK were mediated via c-Src and PDGFR. Pretreatment with PP1 attenuated EV71-stimulated phosphorylation of Src, PDGFR, Akt, and p42/p44 MAPK. Inhibition of PI3K by Wortmannin attenuated EV71-induced Akt and p42/p44 MAPK phosphorylation, but had no effect on PDGFR phosphorylation, suggesting that PDGFR is an upstream and p42/p44 MAPK is a downstream component of PI3K/Akt in these responses. EV71-stimulated NF-κB translocation from the cytoplasm to the nucleus, IkBα degradation and NF-κB promoter activity were attenuated by pretreatment with helenalin, but not AG1296, Wortmannin, and PD98059. EV71-induced c-Jun mRNA expression was attenuated by pretreatment with PD98059, AG1296, or Wortmannin. These results demonstrate that in RBA-1 cells, EV71-induced COX-2 expression associated with PGE2 production is mediated through activation of c-Src/PDGFR/PI3K/Akt/p42/p44 MAPK to initiate the expression of AP-1.

Original languageEnglish
Pages (from-to)376-386
Number of pages11
JournalJournal of Cellular Physiology
Volume224
Issue number2
DOIs
Publication statusPublished - Aug 1 2010
Externally publishedYes

Fingerprint

Mitogen-Activated Protein Kinase 3
Enterovirus
Mitogen-Activated Protein Kinase 1
Transcription Factor AP-1
Phosphatidylinositol 3-Kinases
Astrocytes
Rats
Brain
Phosphorylation
Dinoprostone
Small Interfering RNA
Chemical activation
NF-kappa B
Assays
Degradation
Messenger RNA
wortmannin
Transfection
6,7-dimethoxy-3-phenylquinoxaline
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

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-Ta; Hsieh, Hsi Lung; Yang, Chuen Mao.

In: Journal of Cellular Physiology, Vol. 224, No. 2, 01.08.2010, p. 376-386.

Research output: Contribution to journalArticle

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N2 - Enterovirus 71 (EV71) induces the expression of cyclooxgenase (COX)-2 served as a major neurotoxic factor inCNSinjury. However, the mechanisms underlying EV71-initiated intracellular signaling pathways leading to COX-2 expression remain unknown. Therefore, we investigated the mechanisms underlying EV71-induced COX-2 expression and prostaglandin E2 (PGE2) production in rat brain astrocytes (RBA)-1, determined by Western blotting, RT-PCR, and promoter assay. Here, we reported that EV71-indued COX-2 expression and PGE2 production were attenuated by pretreatment with the inhibitors of c-Src (PP1), PDGFR (AG1296), PI3K (Wortmannin), MEK1/2 (PD98059), NF-kB (helenalin), and AP-1 (Tanshinone) and transfection with shRNA or siRNA of c-Src, PDGFR, p85, c-Jun, c-Fos, ERK1, or ERK2. We further observed that EV71-induced activation of Akt and p42/p44 MAPK were mediated via c-Src and PDGFR. Pretreatment with PP1 attenuated EV71-stimulated phosphorylation of Src, PDGFR, Akt, and p42/p44 MAPK. Inhibition of PI3K by Wortmannin attenuated EV71-induced Akt and p42/p44 MAPK phosphorylation, but had no effect on PDGFR phosphorylation, suggesting that PDGFR is an upstream and p42/p44 MAPK is a downstream component of PI3K/Akt in these responses. EV71-stimulated NF-κB translocation from the cytoplasm to the nucleus, IkBα degradation and NF-κB promoter activity were attenuated by pretreatment with helenalin, but not AG1296, Wortmannin, and PD98059. EV71-induced c-Jun mRNA expression was attenuated by pretreatment with PD98059, AG1296, or Wortmannin. These results demonstrate that in RBA-1 cells, EV71-induced COX-2 expression associated with PGE2 production is mediated through activation of c-Src/PDGFR/PI3K/Akt/p42/p44 MAPK to initiate the expression of AP-1.

AB - Enterovirus 71 (EV71) induces the expression of cyclooxgenase (COX)-2 served as a major neurotoxic factor inCNSinjury. However, the mechanisms underlying EV71-initiated intracellular signaling pathways leading to COX-2 expression remain unknown. Therefore, we investigated the mechanisms underlying EV71-induced COX-2 expression and prostaglandin E2 (PGE2) production in rat brain astrocytes (RBA)-1, determined by Western blotting, RT-PCR, and promoter assay. Here, we reported that EV71-indued COX-2 expression and PGE2 production were attenuated by pretreatment with the inhibitors of c-Src (PP1), PDGFR (AG1296), PI3K (Wortmannin), MEK1/2 (PD98059), NF-kB (helenalin), and AP-1 (Tanshinone) and transfection with shRNA or siRNA of c-Src, PDGFR, p85, c-Jun, c-Fos, ERK1, or ERK2. We further observed that EV71-induced activation of Akt and p42/p44 MAPK were mediated via c-Src and PDGFR. Pretreatment with PP1 attenuated EV71-stimulated phosphorylation of Src, PDGFR, Akt, and p42/p44 MAPK. Inhibition of PI3K by Wortmannin attenuated EV71-induced Akt and p42/p44 MAPK phosphorylation, but had no effect on PDGFR phosphorylation, suggesting that PDGFR is an upstream and p42/p44 MAPK is a downstream component of PI3K/Akt in these responses. EV71-stimulated NF-κB translocation from the cytoplasm to the nucleus, IkBα degradation and NF-κB promoter activity were attenuated by pretreatment with helenalin, but not AG1296, Wortmannin, and PD98059. EV71-induced c-Jun mRNA expression was attenuated by pretreatment with PD98059, AG1296, or Wortmannin. These results demonstrate that in RBA-1 cells, EV71-induced COX-2 expression associated with PGE2 production is mediated through activation of c-Src/PDGFR/PI3K/Akt/p42/p44 MAPK to initiate the expression of AP-1.

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