Journal
CELLULAR SIGNALLING
Volume 22, Issue 2, Pages 234-246Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2009.09.018
Keywords
Viral infection; COX-2; PGE(2); Neurons; MAPKs; Transcription factors
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Funding
- Chang Gung Medical Research Foundation [CMRPD150253, CMRPD150313, CMRPD170491]
- National Science Council, Taiwan [NSC96-2320-B-182-003, NSC96-2320-B-182-047-MY3, NSC972321-B-182-007]
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The enterovirus 71 (EV71) causes severe neurological diseases that were mediated through cyclooxygenase-2 (COX-2) expression in brain. However, the mechanisms underlying EV71-initiated intracellular signaling pathways leading to COX-2 expression remain unknown in neurons. Here we report that exposure of SK-N-SH cells to EV71 increased COX-2 expression and PGE(2) generation in a time- and virus titer-dependent manner, revealed by Western blots real-time PCR, and PGE(2) analyses. These EV71-induced responses were mediated through activation of p42/p44 MAPK, p38 MAPK, JNK, NF-kappa B, and AP-1, revealed by using selective pharmacological inhibitors or transfection with respective siRNAs. Consistently, EV71-stimulated translocation of NF-kappa B into the nucleus and degradation of I kappa B alpha in the cytosol was blocked by pretreatment with the selective inhibitors of MEK1/2 (U0126) and NF-kappa B (Bay11-7085), respectively, suggesting that MEK1/2-p42/p44 MAPK cascade linking to NF-kappa B was involved in COX-2 expression. In addition, EV71-induced AP-1 subunits (c-jun and c-fos mRNA) expression was also attenuated by pretreatment with a selective JNK inhibitor SP600125, suggesting that JNK cascade linking to AP-1 was involved in COX-2 expression induced by EV71. These findings suggested that up-regulation of COX-2 associated with the release of PGE2 from EV71-infected SK-N-SH cells which was mediated through activation of p38 MAPK, JNK, p42/p44 MAPK NF-kappa B. and AP-1 pathways. (C) 2009 Elsevier Inc. All rights reserved.
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