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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
Author(s) -
Tung WeiHsuan,
Lee ITa,
Hsieh HsiLung,
Yang ChuenMao
Publication year - 2010
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22133
Subject(s) - mapk/erk pathway , protein kinase b , proto oncogene tyrosine protein kinase src , pi3k/akt/mtor pathway , nf κb , microbiology and biotechnology , platelet derived growth factor receptor , astrocyte , chemistry , cancer research , neuroscience , biology , signal transduction , receptor , growth factor , central nervous system , biochemistry
Enterovirus 71 (EV71) induces the expression of cyclooxgenase (COX)‐2 served as a major neurotoxic factor in CNS injury. 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 E 2 (PGE 2 ) 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 PGE 2 production were attenuated by pretreatment with the inhibitors of c‐Src (PP1), PDGFR (AG1296), PI3K (Wortmannin), MEK1/2 (PD98059), NF‐κB (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, IκBα 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 PGE 2 production is mediated through activation of c‐Src/PDGFR/PI3K/Akt/p42/p44 MAPK to initiate the expression of AP‐1. J. Cell. Physiol. 224: 376–386, 2010. © 2010 Wiley‐Liss, Inc.