[en] [en] BACKGROUND: Recent studies suggest an important role for neurotransmitters as modulators of inflammation. Neuroinflammatory mediators such as cytokines and molecules of the arachidonic acid pathway are generated and released by microglia. The monoamine norepinephrine reduces the production of cytokines by activated microglia in vitro. However, little is known about the effects of norepinephrine on prostanoid synthesis. In the present study, we investigate the role of norepinephrine on cyclooxygenase- (COX-)2 expression/synthesis and prostaglandin (PG)E2 production in rat primary microglia.
RESULTS: Interestingly, norepinephrine increased COX-2 mRNA, but not protein expression. Norepinephrine strongly enhanced COX-2 expression and PGE2 production induced by lipopolysaccharide (LPS). This effect is likely to be mediated by beta-adrenoreceptors, since beta-, but not alpha-adrenoreceptor agonists produced similar results. Furthermore, beta-adrenoreceptor antagonists blocked the enhancement of COX-2 levels induced by norepinephrine and beta-adrenoreceptor agonists.
CONCLUSIONS: Considering that PGE2 displays different roles in neuroinflammatory and neurodegenerative disorders, norepinephrine may play an important function in the modulation of these processes in pathophysiological conditions.
Disciplines :
Neurology
Author, co-author :
Schlachetzki, Johannes C M; Department of Psychiatry and Psychotherapy, University Hospital of Freiburg, Freiburg, Germany
Fiebich, Bernd L; Department of Psychiatry and Psychotherapy, University Hospital of Freiburg, Freiburg, Germany
Haake, Elisabeth; Department of Psychiatry and Psychotherapy, University Hospital of Freiburg, Freiburg, Germany
de Oliveira, Antonio C P; Department of Psychiatry and Psychotherapy, University Hospital of Freiburg, Freiburg, Germany
Candelario-Jalil, Eduardo; Department of Neurology, University of New Mexico, Albuquerque, NM, United States
HENEKA, Michael ; Department of Neurology, Clinical Neurosciences, University of Bonn Medical Center, Bonn, Germany
Hüll, Michael; Department of Psychiatry and Psychotherapy, University Hospital of Freiburg, Freiburg, Germany
External co-authors :
yes
Language :
English
Title :
Norepinephrine enhances the LPS-induced expression of COX-2 and secretion of PGE2 in primary rat microglia.
We thank Ulrike Götzinger-Berger and Brigitte Günter for excellent technical assistance. Antonio Carlos Pinheiro de Oliveira was supported by CAPES (Brasília/Brazil). This work was supported by KNDD (Kompetenznetz Degenerative Demenzen).
Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005, 308:1314-1318. 10.1126/science.1110647, 15831717.
Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 2005, 8:752-758. 10.1038/nn1472, 15895084.
Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 2007, 10:1387-1394. 10.1038/nn1997, 17965659.
Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 2007, 8:57-69. 10.1038/nrn2038, 17180163.
Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 1990, 249:1431-1433. 10.1126/science.1698311, 1698311.
Fassbender K, Walter S, Kuhl S, Landmann R, Ishii K, Bertsch T, Stalder AK, Muehlhauser F, Liu Y, Ulmer AJ, Rivest S, Lentschat A, Gulbins E, Jucker M, Staufenbiel M, Brechtel K, Walter J, Multhaup G, Penke B, Adachi Y, Hartmann T, Beyreuther K. The LPS receptor (CD14) links innate immunity with Alzheimer's disease. Faseb J 2004, 18:203-205.
Akundi RS, Candelario-Jalil E, Hess S, Hull M, Lieb K, Gebicke-Haerter PJ, Fiebich BL. Signal transduction pathways regulating cyclooxygenase-2 in lipopolysaccharide-activated primary rat microglia. Glia 2005, 51:199-208. 10.1002/glia.20198, 15800925.
Minghetti L, Levi G. Induction of prostanoid biosynthesis by bacterial lipopolysaccharide and isoproterenol in rat microglial cultures. J Neurochem 1995, 65:2690-2698.
Hoozemans JJ, Veerhuis R, Janssen I, van Elk EJ, Rozemuller AJ, Eikelenboom P. The role of cyclo-oxygenase 1 and 2 activity in prostaglandin E(2) secretion by cultured human adult microglia: implications for Alzheimer's disease. Brain Res 2002, 951:218-226. 10.1016/S0006-8993(02)03164-5, 12270500.
Kawano T, Anrather J, Zhou P, Park L, Wang G, Frys KA, Kunz A, Cho S, Orio M, Iadecola C. Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity. Nat Med 2006, 12:225-229. 10.1038/nm1362, 16432513.
Hewett SJ, Uliasz TF, Vidwans AS, Hewett JA. Cyclooxygenase-2 contributes to N-methyl-D-aspartate-mediated neuronal cell death in primary cortical cell culture. J Pharmacol Exp Ther 2000, 293:417-425.
Bazan NG, Colangelo V, Lukiw WJ. Prostaglandins and other lipid mediators in Alzheimer's disease. Prostaglandins Other Lipid Mediat 2002, 68-69:197-210. 10.1016/S0090-6980(02)00031-X, 12432919.
Colangelo V, Schurr J, Ball MJ, Pelaez RP, Bazan NG, Lukiw WJ. Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling. J Neurosci Res 2002, 70:462-473. 10.1002/jnr.10351, 12391607.
Kitamura Y, Shimohama S, Koike H, Kakimura J, Matsuoka Y, Nomura Y, Gebicke-Haerter PJ, Taniguchi T. Increased expression of cyclooxygenases and peroxisome proliferator-activated receptor-gamma in Alzheimer's disease brains. Biochem Biophys Res Commun 1999, 254:582-586. 10.1006/bbrc.1998.9981, 9920782.
Pasinetti GM, Aisen PS. Cyclooxygenase-2 expression is increased in frontal cortex of Alzheimer's disease brain. Neuroscience 1998, 87:319-324. 10.1016/S0306-4522(98)00218-8, 9740394.
Yokota O, Terada S, Ishizu H, Ishihara T, Ujike H, Nakashima H, Nakashima Y, Kugo A, Checler F, Kuroda S. Cyclooxygenase-2 in the hippocampus is up-regulated in Alzheimer's disease but not in variant Alzheimer's disease with cotton wool plaques in humans. Neurosci Lett 2003, 343:175-179.
Ho L, Pieroni C, Winger D, Purohit DP, Aisen PS, Pasinetti GM. Regional distribution of cyclooxygenase-2 in the hippocampal formation in Alzheimer's disease. J Neurosci Res 1999, 57:295-303. 10.1002/(SICI)1097-4547(19990801)57:3<295::AID-JNR1>3.0.CO;2-0, 10412020.
Ho L, Purohit D, Haroutunian V, Luterman JD, Willis F, Naslund J, Buxbaum JD, Mohs RC, Aisen PS, Pasinetti GM. Neuronal cyclooxygenase 2 expression in the hippocampal formation as a function of the clinical progression of Alzheimer disease. Arch Neurol 2001, 58:487-492. 10.1001/archneur.58.3.487, 11255454.
Kaufmann WE, Worley PF, Pegg J, Bremer M, Isakson P. COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci USA 1996, 93:2317-2321. 10.1073/pnas.93.6.2317, 39793, 8637870.
Minghetti L. Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases. J Neuropathol Exp Neurol 2004, 63:901-910.
Tracey KJ, Czura CJ, Ivanova S. Mind over immunity. Faseb J 2001, 15:1575-1576. 10.1096/fj.01-0148hyp, 11427490.
Sternberg EM. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol 2006, 6:318-328. 10.1038/nri1810, 1783839, 16557263.
Pocock JM, Kettenmann H. Neurotransmitter receptors on microglia. Trends Neurosci 2007, 30:527-535. 10.1016/j.tins.2007.07.007, 17904651.
Farber K, Pannasch U, Kettenmann H. Dopamine and noradrenaline control distinct functions in rodent microglial cells. Mol Cell Neurosci 2005, 29:128-138. 10.1016/j.mcn.2005.01.003, 15866053.
Mori K, Ozaki E, Zhang B, Yang L, Yokoyama A, Takeda I, Maeda N, Sakanaka M, Tanaka J. Effects of norepinephrine on rat cultured microglial cells that express alpha1, alpha2, beta1 and beta2 adrenergic receptors. Neuropharmacology 2002, 43:1026-1034. 10.1016/S0028-3908(02)00211-3, 12423672.
Tanaka KF, Kashima H, Suzuki H, Ono K, Sawada M. Existence of functional beta1- and beta2-adrenergic receptors on microglia. J Neurosci Res 2002, 70:232-237. 10.1002/jnr.10399, 12271472.
Prinz M, Hausler KG, Kettenmann H, Hanisch U. beta-adrenergic receptor stimulation selectively inhibits IL-12p40 release in microglia. Brain Res 2001, 899:264-270. 10.1016/S0006-8993(01)02174-6, 11311890.
Chang JY, Liu LZ. Catecholamines inhibit microglial nitric oxide production. Brain Res Bull 2000, 52:525-530. 10.1016/S0361-9230(00)00291-4, 10974492.
Thery C, Dobbertin A, Mallat M. Downregulation of in vitro neurotoxicity of brain macrophages by prostaglandin E2 and a beta-adrenergic agonist. Glia 1994, 11:383-386. 10.1002/glia.440110411, 7960041.
Madrigal JL, Feinstein DL, Dello Russo C. Norepinephrine protects cortical neurons against microglial-induced cell death. J Neurosci Res 2005, 81:390-396. 10.1002/jnr.20481, 15948176.
Dello Russo C, Boullerne AI, Gavrilyuk V, Feinstein DL. Inhibition of microglial inflammatory responses by norepinephrine: effects on nitric oxide and interleukin-1beta production. J Neuroinflammation 2004, 1:9. 10.1186/1742-2094-1-9, 500870, 15285793.
Madrigal JL, Dello Russo C, Gavrilyuk V, Feinstein DL. Effects of noradrenaline on neuronal NOS2 expression and viability. Antioxid Redox Signal 2006, 8:885-892. 10.1089/ars.2006.8.885, 16771678.
Seregi A, Keller M, Jackisch R, Hertting G. Comparison of the prostanoid synthesizing capacity in homogenates from primary neuronal and astroglial cell cultures. Biochem Pharmacol 1984, 33:3315-3318. 10.1016/0006-2952(84)90099-6, 6435636.
Gebicke-Haerter PJ, Bauer J, Schobert A, Northoff H. Lipopolysaccharide-free conditions in primary astrocyte cultures allow growth and isolation of microglial cells. J Neurosci 1989, 9:183-194.
Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987, 162:156-159. 10.1016/0003-2697(87)90021-2, 2440339.
Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970, 227:680-685. 10.1038/227680a0, 5432063.
de Oliveira AC, Candelario-Jalil E, Bhatia HS, Lieb K, Hull M, Fiebich BL. Regulation of prostaglandin E2 synthase expression in activated primary rat microglia: evidence for uncoupled regulation of mPGES-1 and COX-2. Glia 2008, 56:844-855. 10.1002/glia.20658, 18383341.
Kan H, Xie Z, Finkel MS. Norepinephrine-stimulated MAP kinase activity enhances cytokine-induced NO production by rat cardiac myocytes. Am J Physiol 1999, 276:H47-52.
Speidl WS, Toller WG, Kaun C, Weiss TW, Pfaffenberger S, Kastl SP, Furnkranz A, Maurer G, Huber K, Metzler H, Wojta J. Catecholamines potentiate LPS-induced expression of MMP-1 and MMP-9 in human monocytes and in the human monocytic cell line U937: possible implications for peri-operative plaque instability. Faseb J 2004, 18:603-605.
Magocsi M, Vizi ES, Selmeczy Z, Brozik A, Szelenyi J. Multiple G-protein-coupling specificity of beta-adrenoceptor in macrophages. Immunology 2007, 122:503-513. 10.1111/j.1365-2567.2007.02658.x, 2266041, 17949419.
Tan KS, Nackley AG, Satterfield K, Maixner W, Diatchenko L, Flood PM. Beta2 adrenergic receptor activation stimulates pro-inflammatory cytokine production in macrophages via PKA- and NF-kappaB-independent mechanisms. Cell Signal 2007, 19:251-260. 10.1016/j.cellsig.2006.06.007, 16996249.
Szelenyi J, Selmeczy Z, Brozik A, Medgyesi D, Magocsi M. Dual beta-adrenergic modulation in the immune system: stimulus-dependent effect of isoproterenol on MAPK activation and inflammatory mediator production in macrophages. Neurochem Int 2006, 49:94-103. 10.1016/j.neuint.2006.01.009, 16515823.
Morioka N, Tanabe H, Inoue A, Dohi T, Nakata Y. Noradrenaline reduces the ATP-stimulated phosphorylation of p38 MAP kinase via beta-adrenergic receptors-cAMP-protein kinase A-dependent mechanism in cultured rat spinal microglia. Neurochem Int 2009, 55:226-234. 10.1016/j.neuint.2009.03.004, 19524113.
Ridley SH, Dean JL, Sarsfield SJ, Brook M, Clark AR, Saklatvala J. A p38 MAP kinase inhibitor regulates stability of interleukin-1-induced cyclooxygenase-2 mRNA. FEBS Lett 1998, 439:75-80. 10.1016/S0014-5793(98)01342-8, 9849881.
Weichhart T, Costantino G, Poglitsch M, Rosner M, Zeyda M, Stuhlmeier KM, Kolbe T, Stulnig TM, Horl WH, Hengstschlager M, Müller M, Säemann MD. The TSC-mTOR signaling pathway regulates the innate inflammatory response. Immunity 2008, 29:565-577. 10.1016/j.immuni.2008.08.012, 18848473.
Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004, 18:1926-1945. 10.1101/gad.1212704, 15314020.
Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, Tran T, Ubeda O, Ashe KH, Frautschy SA, Cole GM. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. J Neurosci 2000, 20:5709-5714.
Scali C, Prosperi C, Vannucchi MG, Pepeu G, Casamenti F. Brain inflammatory reaction in an animal model of neuronal degeneration and its modulation by an anti-inflammatory drug: implication in Alzheimer's disease. Eur J Neurosci 2000, 12:1900-1912. 10.1046/j.1460-9568.2000.00075.x, 10886331.
Teismann P, Tieu K, Choi DK, Wu DC, Naini A, Hunot S, Vila M, Jackson-Lewis V, Przedborski S. Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration. Proc Natl Acad Sci USA 2003, 100:5473-5478. 10.1073/pnas.0837397100, 154369, 12702778.
Wang T, Pei Z, Zhang W, Liu B, Langenbach R, Lee C, Wilson B, Reece JM, Miller DS, Hong JS. MPP+-induced COX-2 activation and subsequent dopaminergic neurodegeneration. FASEB J 2005, 19:1134-1136. 10.1096/fj.04-2370com, 15845609.
Manabe Y, Anrather J, Kawano T, Niwa K, Zhou P, Ross ME, Iadecola C. Prostanoids, not reactive oxygen species, mediate COX-2-dependent neurotoxicity. Ann Neurol 2004, 55:668-675. 10.1002/ana.20078, 15122707.
Carlson NG. Neuroprotection of cultured cortical neurons mediated by the cyclooxygenase-2 inhibitor APHS can be reversed by a prostanoid. J Neurosci Res 2003, 71:79-88. 10.1002/jnr.10465, 12478616.
Kim EJ, Kwon KJ, Park JY, Lee SH, Moon CH, Baik EJ. Neuroprotective effects of prostaglandin E2 or cAMP against microglial and neuronal free radical mediated toxicity associated with inflammation. J Neurosci Res 2002, 70:97-107. 10.1002/jnr.10373, 12237868.
Zhang B, Yang L, Konishi Y, Maeda N, Sakanaka M, Tanaka J. Suppressive effects of phosphodiesterase type IV inhibitors on rat cultured microglial cells: comparison with other types of cAMP-elevating agents. Neuropharmacology 2002, 42:262-269. 10.1016/S0028-3908(01)00174-5, 11804623.
Akaike A, Kaneko S, Tamura Y, Nakata N, Shiomi H, Ushikubi F, Narumiya S. Prostaglandin E2 protects cultured cortical neurons against N-methyl-D-aspartate receptor-mediated glutamate cytotoxicity. Brain Res 1994, 663:237-243. 10.1016/0006-8993(94)91268-8, 7874506.
Cazevieille C, Muller A, Meynier F, Dutrait N, Bonne C. Protection by prostaglandins from glutamate toxicity in cortical neurons. Neurochem Int 1994, 24:395-398. 10.1016/0197-0186(94)90118-X, 7914788.
Craft JM, Watterson DM, Van Eldik LJ. Neuroinflammation: a potential therapeutic target. Expert Opin Ther Targets 2005, 9:887-900. 10.1517/14728222.9.5.887, 16185146.
Hoozemans JJ, Veerhuis R, Rozemuller JM, Eikelenboom P. Neuroinflammation and regeneration in the early stages of Alzheimer's disease pathology. Int J Dev Neurosci 2006, 24:157-165. 10.1016/j.ijdevneu.2005.11.001, 16384684.
Hoozemans JJ, O'Banion MK. The role of COX-1 and COX-2 in Alzheimer's disease pathology and the therapeutic potentials of non-steroidal anti-inflammatory drugs. Curr Drug Targets CNS Neurol Disord 2005, 4:307-315. 10.2174/1568007054038201, 15975032.
Minghetti L. Role of inflammation in neurodegenerative diseases. Curr Opin Neurol 2005, 18:315-321. 10.1097/01.wco.0000169752.54191.97, 15891419.
Montine TJ, Woltjer RL, Pan C, Montine KS, Zhang J. Liquid chromatography with tandem mass spectrometry-based proteomic discovery in aging and Alzheimer's disease. NeuroRx 2006, 3:336-343. 10.1016/j.nurx.2006.05.002, 16815217.
Martin BK, Szekely C, Brandt J, Piantadosi S, Breitner JC, Craft S, Evans D, Green R, Mullan M. Cognitive function over time in the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT): results of a randomized, controlled trial of naproxen and celecoxib. Arch Neurol 2008, 65:896-905. 10.1001/archneur.65.12.noc80051, 18474729.
Thal LJ, Ferris SH, Kirby L, Block GA, Lines CR, Yuen E, Assaid C, Nessly ML, Norman BA, Baranak CC, Reines SA. A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology 2005, 30:1204-1215. 10.1038/sj.npp.1300690, 15742005.
Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, Farlow MR, Jin S, Thomas RG, Thal LJ. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. Jama 2003, 289:2819-2826. 10.1001/jama.289.21.2819, 12783912.
Reines SA, Block GA, Morris JC, Liu G, Nessly ML, Lines CR, Norman BA, Baranak CC. Rofecoxib: no effect on Alzheimer's disease in a 1-year, randomized, blinded, controlled study. Neurology 2004, 62:66-71.
Narumiya S, Sugimoto Y, Ushikubi F. Prostanoid receptors: structures, properties, and functions. Physiol Rev 1999, 79:1193-1226.
Slawik H, Volk B, Fiebich B, Hull M. Microglial expression of prostaglandin EP3 receptor in excitotoxic lesions in the rat striatum. Neurochem Int 2004, 45:653-660. 10.1016/j.neuint.2004.04.007, 15234107.
Shie FS, Montine KS, Breyer RM, Montine TJ. Microglial EP2 is critical to neurotoxicity from activated cerebral innate immunity. Glia 2005, 52:70-77. 10.1002/glia.20220, 15920732.
Baker JG. The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2 and beta3 adrenoceptors. Br J Pharmacol 2005, 144:317-322. 10.1038/sj.bjp.0706048, 1576008, 15655528.
Hieble JP. Recent advances in identification and characterization of beta-adrenoceptor agonists and antagonists. Curr Top Med Chem 2007, 7:207-216. 10.2174/156802607779318208, 17266607.
Sears MR, Lotvall J. Past, present and future--beta2-adrenoceptor agonists in asthma management. Respir Med 2005, 99:152-170. 10.1016/j.rmed.2004.07.003, 15715182.
Caggiano AO, Kraig RP. Prostaglandin E receptor subtypes in cultured rat microglia and their role in reducing lipopolysaccharide-induced interleukin-1beta production. J Neurochem 1999, 72:565-575. 10.1046/j.1471-4159.1999.0720565.x, 9930728.
Colton CA, Chernyshev ON. Inhibition of microglial superoxide anion production by isoproterenol and dexamethasone. Neurochem Int 1996, 29:43-53. 10.1016/0197-0186(95)00139-5, 8808788.
Minghetti L, Nicolini A, Polazzi E, Creminon C, Maclouf J, Levi G. Prostaglandin E2 downregulates inducible nitric oxide synthase expression in microglia by increasing cAMP levels. Adv Exp Med Biol 1997, 433:181-184.
Scales WE, Chensue SW, Otterness I, Kunkel SL. Regulation of monokine gene expression: prostaglandin E2 suppresses tumor necrosis factor but not interleukin-1 alpha or beta-mRNA and cell-associated bioactivity. J Leukoc Biol 1989, 45:416-421.
Pouw Kraan TC, Boeije LC, Smeenk RJ, Wijdenes J, Aarden LA. Prostaglandin-E2 is a potent inhibitor of human interleukin 12 production. J Exp Med 1995, 181:775-779. 10.1084/jem.181.2.775, 2191857, 7836930.
Levi G, Minghetti L, Aloisi F. Regulation of prostanoid synthesis in microglial cells and effects of prostaglandin E2 on microglial functions. Biochimie 1998, 80:899-904. 10.1016/S0300-9084(00)88886-0, 9893949.
Hasko G, Shanley TP, Egnaczyk G, Nemeth ZH, Salzman AL, Vizi ES, Szabo C. Exogenous and endogenous catecholamines inhibit the production of macrophage inflammatory protein (MIP) 1 alpha via a beta adrenoceptor mediated mechanism. Br J Pharmacol 1998, 125:1297-1303. 10.1038/sj.bjp.0702179, 1565690, 9863660.
Bondareff W, Mountjoy CQ, Roth M. Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia. Neurology 1982, 32:164-168.
