Abstract
The transcription factor NF-κB is activated in neurons and promotes neuronal death in cerebral ischemia. Its target genes include cytosolic phospholipase A-2 (cPLA-2), cyclooxygenase-2 (COX-2), and microsomal prostaglandin E2 synthase-1 (mPGES-1), three genes that are involved in the synthesis of prostaglandin E2 (PGE2). In our study, oxygen glucose deprivation (OGD), an in vitro model of cerebral ischemia, activated NF-κB activity in primary cortical neurons. Furthermore, OGD and the NF-κB activator tumor necrosis factor stimulated the expression of cPLA-2, cyclooxygenase-2 (COX-2), and mPGES-1 and increased the release of PGE2 from neurons. Expression of a constitutively active IκB kinase (IKK) or the NF-κB subunit p65 in neurons stimulated the transcription of cPLA-2, COX-2, and mPGES-1. Finally, inhibition of IKK in neurons blocked the induction of the three genes involved in PGE2 synthesis in vivo. In summary, NF-κB controls the neuronal expression of three genes involved in PGE2 synthesis in cerebral ischemia.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ackerman WEIV, Summerfield TLS, Vandre DD, Robinson JM, Kniss DA (2008) Nuclear factor-kappa B regulates inducible prostaglandin E synthase expression in human amnion mesenchymal cells. Biol Reprod 78:68–76
Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3:745–756
Araki E, Forster C, Dubinsky JM, Ross ME, Iadecola C (2001) Cyclooxygenase-2 inhibitor NS-398 protects neuronal cultures from lipopolysaccharide-induced neurotoxicity. Stroke 32:2370–2375
Barone FC, Feuerstein GZ (1999) Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab 19:819–834
Baumann B, Wagner M, Aleksic T, von Wichert G, Weber CK, Adler G, Wirth T (2007) Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo. J Clin Invest 117:1502–1513
Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69
Bonventre JV, Huang Z, Taheri MR, O'Leary E, Li E, Moskowitz MA, Sapirstein A (1997) Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2. Nature 390:622–625
Catley MC, Chivers JE, Cambridge LM, Holden N, Slater DM, Staples KJ, Bergmann MW, Loser P, Barnes PJ, Newton R (2003) IL-1beta-dependent activation of NF-kappaB mediates PGE2 release via the expression of cyclooxygenase-2 and microsomal prostaglandin E synthase. FEBS Lett 547:75–79
Chamorro A, Hallenbeck J (2006) The harms and benefits of inflammatory and immune responses in vascular disease. Stroke 37:291–293
de Oliveira ACP, Eduardo C-J, Bhatia HS, Klaus L, Michael H, Fiebich BL (2008) Regulation of prostaglandin E1 synthase expression in activated primary rat microglia: evidence for uncoupled regulation of mPGES-1 and COX-2. Glia 56:844–855
Endres M, Engelhardt B, Koistinaho J, Lindvall O, Meairs S, Mohr JP, Planas A, Rothwell N, Schwaninger M, Schwab ME, Vivien D, Wieloch T, Dirnagl U (2008) Improving outcome after stroke: overcoming the translational roadblock. Cerebrovasc Dis 25:268–278
Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D (2008) Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 359:1317–1329
Hallenbeck JM (2002) The many faces of tumor necrosis factor in stroke. Nat Med 8:1363–1368
Herrmann O, Baumann B, De Lorenzi R, Muhammad S, Zhang W, Kleesiek J, Malfertheiner M, Köhrmann M, Potrovita I, Maegele I, Beyer C, Burke JR, Hasan MT, Bujard H, Wirth T, Pasparakis M, Schwaninger M (2005) IKK mediates ischemia-induced neuronal cell death. Nat Med 11:1322–1329
Hsieh H-L, Wu C-Y, Hwang T-L, Yen M-H, Parker P, Yang C-M (2006) BK-induced cytosolic phospholipase A2 expression via sequential PKC-delta, p42/p44 MAPK, and NF-kappaB activation in rat brain astrocytes. J Cell Physiol 206:246–254
Iadecola C, Niwa K, Nogawa S, Zhao X, Nagayama M, Araki E, Morham S, Ross ME (2001) Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice. Proc Natl Acad Sci U S A 98:1294–1299
Ikeda-Matsuo Y, Ota A, Fukada T, Uematsu S, Akira S, Sasaki Y (2006) Microsomal prostaglandin E synthase-1 is a critical factor of stroke-reperfusion injury. Proc Natl Acad Sci U S A 103:11790–11795
Inta I, Paxian S, Maegele I, Zhang W, Pizzi M, Spano P, Sarnico I, Muhammad S, Herrmann O, Inta D, Baumann B, Liou H-C, Schmid RM, Schwaninger M (2006) Bim and noxa are candidates to mediate the deleterious effect of the NF-{kappa}B subunit RelA in cerebral ischemia. J Neurosci 26:12896–12903
Jatana M, Giri S, Ansari MA, Elango C, Singh AK, Singh I, Khan M (2006) Inhibition of NF-kB activation by 5-lipoxygenase inhibitors protects brain against injury in a rat model of focal cerebral ischemia. J Neuroinflammation 3:12
Juttler E, Kohrmann M, Schellinger PD (2006) Therapy for early reperfusion after stroke. Nat Clin Pract Cardiovasc Med 3:656–663
Kaltschmidt B, Linker RA, Deng J, Kaltschmidt C (2002) Cyclooxygenase-2 is a neuronal target gene of NF-kappaB. BMC Mol Biol 3:16
Kawano T, Anrather J, Zhou P, Park L, Wang G, Frys KA, Kunz A, Cho S, Orio M, Iadecola C (2006) Prostaglandin E(2) EP1 receptors: downstream effectors of COX-2 neurotoxicity. Nat Med 12:225–229
Lang MF, Schneider A, Krüger C, Schmid R, Dziarski R, Schwaninger M (2008) Peptidoglycan recognition protein-S (PGRP-S) is upregulated by NF-κB. Neurosci Lett 430:138–141
Liu D, Wu L, Breyer R, Mattson MP, Andreasson K (2005) Neuroprotection by the PGE2 EP2 receptor in permanent focal cerebral ischemia. Ann Neurol 57:758–761
Manabe Y, Anrather J, Kawano T, Niwa K, Zhou P, Ross ME, Iadecola C (2004) Prostanoids, not reactive oxygen species, mediate COX-2-dependent neurotoxicity. Ann Neurol 55:668–675
Mattson MP, Camandola S (2001) NF-kappaB in neuronal plasticity and neurodegenerative disorders. J Clin Invest 107:247–254
McCullough L, Wu L, Haughey N, Liang X, Hand T, Wang Q, Breyer RM, Andreasson K (2004) Neuroprotective function of the PGE2 EP2 receptor in cerebral ischemia. J Neurosci 24:257–268
Miettinen S, Fusco FR, Yrjanheikki J, Keinanen R, Hirvonen T, Roivainen R, Narhi M, Hokfelt T, Koistinaho J (1997) Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N-methyl-D-aspartic acid-receptors and phospholipase A2. PNAS 94:6500–6505
Morri H, Ozaki M, Watanabe Y (1994) 5′-flanking region surrounding a human cytosolic phospholipase A2 gene. Biochem Biophys Res Commun 205:6–11
Naraba H, Yokoyama C, Tago N, Murakami M, Kudo I, Fueki M, Oh-Ishi S, Tanabe T (2002) Transcriptional regulation of the membrane-associated prostaglandin E2 synthase gene. Essential role of the transcription factor Egr-1. J Biol Chem 277:28601–28608
Nito C, Kamada H, Endo H, Niizuma K, Myer DJ, Chan PH (2008) Role of the p38 mitogen-activated protein kinase/cytosolic phospholipase A2 signaling pathway in blood-brain barrier disruption after focal cerebral ischemia and reperfusion. J Cereb Blood Flow Metab 28:1686–1696
Nogawa S, Zhang F, Ross ME, Iadecola C (1997) Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage. J Neurosci 17:2746–2755
Nurmi A, Lindsberg PJ, Koistinaho M, Zhang W, Juettler E, Karjalainen-Lindsberg ML, Weih F, Frank N, Schwaninger M, Koistinaho J (2004) Nuclear factor-kappaB contributes to infarction after permanent focal ischemia. Stroke 35:987–991
Potrovita I, Zhang W, Burkly L, Hahm K, Lincecum J, Wang MZ, Maurer MH, Rossner M, Schneider A, Schwaninger M (2004) Tumor necrosis factor-like weak inducer of apoptosis-induced neurodegeneration. J Neurosci 24:8237–8244
Ridder DA, Schwaninger M (2008) NF-kappaB signaling in cerebral ischemia. Neuroscience 158:995–1006
Sallmann S, Juttler E, Prinz S, Petersen N, Knopf U, Weiser T, Schwaninger M (2000) Induction of interleukin-6 by depolarization of neurons. J Neurosci 20:8637–8642
Samson Y, Lapergue B, Hosseini H (2005) Inflammation and ischaemic stroke: current status and future perspectives. Rev Neurol (Paris) 161:1177–1182
Sang N, Zhang J, Marcheselli V, Bazan NG, Chen C (2005) Postsynaptically synthesized prostaglandin E2 (PGE2) modulates hippocampal synaptic transmission via a presynaptic PGE2 EP2 receptor. J Neurosci 25:9858–9870
Sarnico I, Lanzillotta A, Boroni F, Benarese M, Alghisi M, Schwaninger M, Inta I, Battistin L, Spano PF, Pizzi M (2009) NF-κB p50/RelA- and c-Rel-containing dimers: opposite regulators of neuron vulnerability to ischemia. J Neurochem 108:475–485
Schneider A, Martin-Villalba A, Weih F, Vogel J, Wirth T, Schwaninger M (1999) NF-κB is activated and promotes cell death in focal cerebral ischemia. Nat Med 5:554–559
Stephenson D, Rash K, Smalstig B, Roberts E, Johnstone E, Sharp J, Panetta J, Little S, Kramer R, Clemens J (1999) Cytosolic phospholipase A2 is induced in reactive glia following different forms of neurodegeneration. Glia 27:110–128
Yokota C, Kaji T, Kuge Y, Inoue H, Tamaki N, Minematsu K (2004) Temporal and topographic profiles of cyclooxygenase-2 expression during 24 h of focal brain ischemia in rats. Neurosci Lett 357:219–222
Zhang W, Potrovita I, Tarabin V, Herrmann O, Beer V, Weih F, Schneider A, Schwaninger M (2005) Neuronal activation of NF-κB contributes to cell death in cerebral ischemia. J Cereb Blood Flow Metab 25:30–40
Zhou P, Qian L, Chou T, Iadecola C (2008) Neuroprotection by PGE2 receptor EP1 inhibition involves the PTEN/AKT pathway. Neurobiol Dis 29:543–551
Acknowledgment
This work was supported by a grant from Deutsche Forschungsgemeinschaft (Schw 416/5-1). WB was funded by the Egyptian Ministry for Higher Education. We thank Dr. Hiroaki Naraba, Iwate Medical University, Japan for providing mPGES-luc.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Barakat, W., Herrmann, O., Baumann, B. et al. NF-κB induces PGE2-synthesizing enzymes in neurons. Naunyn-Schmied Arch Pharmacol 380, 153–160 (2009). https://doi.org/10.1007/s00210-009-0421-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-009-0421-0