Enterovirus 71 induces COX-2 expression via MAPKs, NF-kappaB, and AP-1 in SK-N-SH cells: Role of PGE(2) in viral replication.
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 blot, real-time PCR, and PGE(2) analyses. These EV71-induced responses were mediated through activation of p42/p44 MAPK, p38 MAPK, JNK, NF-kappaB, and AP-1, revealed by using selective pharmacological inhibitors or transfection with respective siRNAs. Consistently, EV71-stimulated translocation of NF-kappaB into the nucleus and degradation of IkappaBalpha in the cytosol was blocked by pretreatment with the selective inhibitors of MEK1/2 (U0126) and NF-kappaB (Bay11-7085), respectively, suggesting that MEK1/2-p42/p44 MAPK cascade linking to NF-kappaB 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 PGE(2) from EV71-infected SK-N-SH cells which was mediated through activation of p38 MAPK, JNK, p42/p44 MAPK, NF-kappaB, and AP-1 pathways.
Tung
Wei-Hsuan
WH
Department of Physiology and Pharmacology, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.
Hsieh
Hsi-Lung
HL
Yang
Chuen-Mao
CM
D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism / Q000502:physiology*; D029821:Enterovirus A, Human; D004769:Enterovirus Infections / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014779:Virus Replication; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016328:NF-kappa B; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone