Interleukin-1beta induces cyclooxygenase-2 and prostaglandin E(2) synthesis in human neuroblastoma cells: involvement of p38 mitogen-activated protein kinase and nuclear factor-kappaB.
Prostaglandins (PGs), which are generated by the enzymatic activity of cyclooxygenase (COX)-1 and -2, modulate several functions in the CNS such as the generation of fever, the sleep/wake cycle, and the perception of pain. Moreover, the neuronal induction of COX-2 has been linked to neuroinflammatory aspects of Alzheimer's disease (AD). The regulation of COX expression in neuronal cells is only partly understood and has been mainly linked to synaptic activity. In pathophysiological situations, however, cytokines may be potent stimulators of neuronal COX expression. Here we show that interleukin (IL)-1beta induces COX-2 mRNA and protein synthesis and the release of PGE(2) in the human neuroblastoma cell line SK-N-SH. We further demonstrate that both a free radical scavenger and an inhibitor of p38 mitogen-activated protein kinase (MAPK) reduce IL-1beta-induced synthesis of COX-2. IL-1beta induces p38 MAPK phosphorylation and activation of the nuclear factor-kappaB independently from each other. Our data suggest that IL-1beta-induced COX-2 expression in SK-N-SH cells is regulated by different mechanisms, presumably involving mRNA transcription and mRNA stability. The ability of p38 MAPK to augment COX-2 expression in human neuroblastoma cells, as shown here, suggests that p38 MAPK may be involved in neuronal expression of COX-2 in AD.
Fiebich
B L
BL
Department of Psychiatry, University of Freiburg Medical School, Freiburg, Germany. bernd_fiebich@psyallg.ukl.uni-freiburg.de
Mueksch
B
B
Boehringer
M
M
Hüll
M
M
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D051546:Cyclooxygenase 2; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism* / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009447:Neuroblastoma; D011392:Proline / Q000031:analogs & derivatives*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013859:Thiocarbamates / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007093:Imidazoles; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D011725:Pyridines; D011759:Pyrrolidines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013859:Thiocarbamates; C066229:prolinedithiocarbamate; C020972:pyrrolidine dithiocarbamic acid; D003907:Dexamethasone; D011392:Proline; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole