Regulation of nociceptin/orphanin FQ gene expression in astrocytes by ceramide.
Ceramide is generated in response to inflammatory mediators and oxidative stress. Since these stimuli dramatically increase nociceptin/orphanin FQ (N/OFQ) gene expression in astrocytes we evaluated the regulation of N/OFQ by ceramide and the signaling mechanisms involved. We found that ceramide induced N/OFQ mRNA levels 22-fold after 24 h. In astrocytes ceramide stimulated the JNK, p38 and ERK MAP kinase pathways and also led to the activation of the transcription factors CREB and NFkappaB. Using specific inhibitors of signaling pathways we determined that N/OFQ gene induction is mediated by ERK and p38 MAP kinases. ERK activation may be induced by protein kinase C and it leads to CREB phosphorylation. The NFkappaB pathway also appears to be crucial for ceramide-induced N/OFQ gene expression.
Buzas
Beata
B
Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA. bbuzas@usuhs.mil
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology*; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism* / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D004660:Encephalitis / Q000201:enzymology / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D018847:Opioid Peptides / Q000235:genetics*; D018384:Oxidative Stress / Q000502:physiology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015533:Transcriptional Activation; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases; D000097629:Nociceptin
D002518:Ceramides; D017362:Cyclic AMP Response Element-Binding Protein; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D018847:Opioid Peptides; D012333:RNA, Messenger; D048051:p38 Mitogen-Activated Protein Kinases; D000097629:Nociceptin