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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2008

Open Access 01-12-2008 | Research

Neuroinflammatory response to lipopolysaccharide is exacerbated in mice genetically deficient in cyclooxygenase-2

Authors: Saba Aid, Robert Langenbach, Francesca Bosetti

Published in: Journal of Neuroinflammation | Issue 1/2008

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Abstract

Background

Cyclooxygenases (COX) -1 and -2 are key mediators of the inflammatory response in the central nervous system. Since COX-2 is inducible by inflammatory stimuli, it has been traditionally considered as the most appropriate target for anti-inflammatory drugs. However, the specific roles of COX-1 and COX-2 in modulating a neuroinflammatory response are unclear. Recently, we demonstrated that COX-1 deficient mice show decreased neuroinflammatory response and neuronal damage in response to lipopolysaccharide (LPS).

Methods

In this study, we investigated the role of COX-2 in the neuroinflammatory response to intracerebroventricular-injected LPS (5 μg), a model of direct activation of innate immunity, using COX-2 deficient (COX-2-/-) and wild type (COX-2+/+) mice, as well as COX-2+/+ mice pretreated for 6 weeks with celecoxib, a COX-2 selective inhibitor.

Results

Twenty-four hours after LPS injection, COX-2-/- mice showed increased neuronal damage, glial cell activation, mRNA and protein expression of markers of inflammation and oxidative stress, such as cytokines, chemokines, iNOS and NADPH oxidase. Brain protein levels of IL-1β, NADPH oxidase subunit p67phox, and phosphorylated-signal transducer and activator of transcription 3 (STAT3) were higher in COX-2-/- and in celecoxib-treated mice, compared to COX-2+/+ mice. The increased neuroinflammatory response in COX-2-/- mice was likely mediated by the upregulation of STAT3 and suppressor of cytokine signaling 3 (SOCS3).

Conclusion

These results show that inhibiting COX-2 activity can exacerbate the inflammatory response to LPS, possibly by increasing glial cells activation and upregulating the STAT3 and SOCS3 pathways in the brain.
Appendix
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Literature
1.
Morita I: Distinct functions of COX-1 and COX-2. Prostaglandins Other Lipid Mediat. 2002, 68–69: 165-175. 10.1016/S0090-6980(02)00029-1.CrossRefPubMed
2.
Kaufmann WE, Andreasson KI, Isakson PC, Worley PF: Cyclooxygenases and the central nervous system. Prostaglandins. 1997, 54: 601-624. 10.1016/S0090-6980(97)00128-7.CrossRefPubMed
3.
Yamagata K, Andreasson KI, Kaufmann WE, Barnes CA, Worley PF: Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron. 1993, 11: 371-386. 10.1016/0896-6273(93)90192-T.CrossRefPubMed
4.
5.
Hayaishi O, Matsumura H: Prostaglandins and sleep. Adv Neuroimmunol. 1995, 5: 211-216. 10.1016/0960-5428(95)00010-Y.CrossRefPubMed
6.
Minghetti L: Role of COX-2 in inflammatory and degenerative brain diseases. Subcell Biochem. 2007, 42: 127-141.CrossRefPubMed
7.
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.PubMedCentralCrossRefPubMed
8.
Stefanovic B, Bosetti F, Silva AC: Modulatory role of cyclooxygenase-2 in cerebrovascular coupling. Neuroimage. 2006, 32: 23-32. 10.1016/j.neuroimage.2006.03.014.CrossRefPubMed
9.
Ojeda SR, Urbanski HF, Junier MP, Capdevila J: The role of arachidonic acid and its metabolites in the release of neuropeptides. Ann N Y Acad Sci. 1989, 559: 192-207. 10.1111/j.1749-6632.1989.tb22609.x.CrossRefPubMed
10.
Graham SH, Hickey RW: Cyclooxygenases in central nervous system diseases: a special role for cyclooxygenase 2 in neuronal cell death. Arch Neurol. 2003, 60: 628-630. 10.1001/archneur.60.4.628.CrossRefPubMed
11.
Phillis JW, Horrocks LA, Farooqui AA: Cyclooxygenases, lipoxygenases, and epoxygenases in CNS: their role and involvement in neurological disorders. Brain Res Rev. 2006, 52: 201-243. 10.1016/j.brainresrev.2006.02.002.CrossRefPubMed
12.
Choi SH, Langenbach R, Bosetti F: Genetic deletion or pharmacological inhibition of cyclooxygenase-1 attenuate lipopolysaccharide-induced inflammatory response and brain injury. FASEB J. 2008, 22: 1491-1501. 10.1096/fj.07-9411com.PubMedCentralCrossRefPubMed
13.
Li S, Wang Y, Matsumura K, Ballou LR, Morham SG, Blatteis CM: The febrile response to lipopolysaccharide is blocked in cyclooxygenase-2(-/-), but not in cyclooxygenase-1(-/-) mice. Brain Res. 1999, 825: 86-94. 10.1016/S0006-8993(99)01225-1.CrossRefPubMed
14.
Blais V, Turrin NP, Rivest S: Cyclooxygenase 2 (COX-2) inhibition increases the inflammatory response in the brain during systemic immune stimuli. J Neurochem. 2005, 95: 1563-1574. 10.1111/j.1471-4159.2005.03480.x.CrossRefPubMed
15.
Milatovic D, VanRollins M, Li K, Montine KS, Montine TJ: Suppression of murine cerebral F2-isoprostanes and F4-neuroprostanes from excitotoxicity and innate immune response in vivo by alpha- or gamma-tocopherol. J Chromatogr B Analyt Technol Biomed Life Sci. 2005, 827: 88-93. 10.1016/j.jchromb.2005.03.037.CrossRefPubMed
16.
Milatovic D, Zaja-Milatovic S, Montine KS, Shie FS, Montine TJ: Neuronal oxidative damage and dendritic degeneration following activation of CD14-dependent innate immune response in vivo. J Neuroinflammation. 2004, 1: 20-10.1186/1742-2094-1-20.PubMedCentralCrossRefPubMed
17.
Bluthe RM, Laye S, Michaud B, Combe C, Dantzer R, Parnet P: Role of interleukin-1beta and tumour necrosis factor-alpha in lipopolysaccharide-induced sickness behaviour: a study with interleukin-1 type I receptor-deficient mice. Eur J Neurosci. 2000, 12: 4447-4456. 10.1046/j.1460-9568.2000.01348.x.PubMed
18.
Abdulla D, Goralski KB, Del Busto Cano EG, Renton KW: The signal transduction pathways involved in hepatic cytochrome P450 regulation in the rat during a lipopolysaccharide-induced model of central nervous system inflammation. Drug Metab Dispos. 2005, 33: 1521-1531. 10.1124/dmd.105.004564.CrossRefPubMed
19.
Montine TJ, Milatovic D, Gupta RC, Valyi-Nagy T, Morrow JD, Breyer RM: Neuronal oxidative damage from activated innate immunity is EP2 receptor-dependent. J Neurochem. 2002, 83: 463-470. 10.1046/j.1471-4159.2002.01157.x.CrossRefPubMed
20.
Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, Volpe JJ, Vartanian T: Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci USA. 2003, 100: 8514-8519. 10.1073/pnas.1432609100.PubMedCentralCrossRefPubMed
21.
Hosoi T, Okuma Y, Kawagishi T, Qi X, Matsuda T, Nomura Y: Bacterial endotoxin induces STAT3 activation in the mouse brain. Brain Res. 2004, 1023: 48-53. 10.1016/j.brainres.2004.06.076.CrossRefPubMed
22.
Quan N, Sundar SK, Weiss JM: Induction of interleukin-1 in various brain regions after peripheral and central injections of lipopolysaccharide. J Neuroimmunol. 1994, 49: 125-134. 10.1016/0165-5728(94)90188-0.CrossRefPubMed
23.
Luster AD: Chemokines – chemotactic cytokines that mediate inflammation. N Engl J Med. 1998, 338: 436-445. 10.1056/NEJM199802123380706.CrossRefPubMed
24.
Milatovic D, Zaja-Milatovic S, Montine KS, Horner PJ, Montine TJ: Pharmacologic suppression of neuronal oxidative damage and dendritic degeneration following direct activation of glial innate immunity in mouse cerebrum. J Neurochem. 2003, 87: 1518-1526.CrossRefPubMed
25.
Perry VH, Newman TA, Cunningham C: The impact of systemic infection on the progression of neurodegenerative disease. Nat Rev Neurosci. 2003, 4: 103-112. 10.1038/nrn1032.CrossRefPubMed
26.
Morham SG, Langenbach R, Loftin CD, Tiano HF, Vouloumanos N, Jennette JC, Mahler JF, Kluckman KD, Ledford A, Lee CA, Smithies O: Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. Cell. 1995, 83: 473-482. 10.1016/0092-8674(95)90125-6.CrossRefPubMed
27.
Toscano CD, Prabhu VV, Langenbach R, Becker KG, Bosetti F: Differential gene expression patterns in cyclooxygenase-1 and cyclooxygenase-2 deficient mouse brain. Genome Biol. 2007, 8: R14-10.1186/gb-2007-8-1-r14.PubMedCentralCrossRefPubMed
28.
Toscano CD, Ueda Y, Tomita YA, Vicini S, Bosetti F: Altered GABAergic neurotransmission is associated with increased kainate-induced seizure in prostaglandin-endoperoxide synthase-2 deficient mice. Brain Res Bull. 2008, 75: 598-609. 10.1016/j.brainresbull.2007.10.004.PubMedCentralCrossRefPubMed
29.
Goralski KB, Abdulla D, Sinal CJ, Arsenault A, Renton KW: Toll-like receptor-4 regulation of hepatic Cyp3a11 metabolism in a mouse model of LPS-induced CNS inflammation. Am J Physiol Gastrointest Liver Physiol. 2005, 289: G434-443. 10.1152/ajpgi.00562.2004.CrossRefPubMed
30.
Paxinos G, Franklin KBJ, (Eds.): The mouse brain in stereotaxic coordinates. 2001, San Diego: Academic Press, 2
31.
Schmued LC, Hopkins KJ: Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res. 2000, 874: 123-130. 10.1016/S0006-8993(00)02513-0.CrossRefPubMed
32.
Bosetti F, Langenbach R, Weerasinghe GR: Prostaglandin E2 and microsomal prostaglandin E synthase-2 expression are decreased in the cyclooxygenase-2-deficient mouse brain despite compensatory induction of cyclooxygenase-1 and Ca2+-dependent phospholipase A2. J Neurochem. 2004, 91: 1389-1397. 10.1111/j.1471-4159.2004.02829.x.CrossRefPubMed
33.
Choi SH, Langenbach R, Bosetti F: Cyclooxygenase-1 and -2 enzymes differentially regulate the brain upstream NF-kappa B pathway and downstream enzymes involved in prostaglandin biosynthesis. J Neurochem. 2006, 98: 801-811. 10.1111/j.1471-4159.2006.03926.x.PubMedCentralCrossRefPubMed
34.
Aid S, Bosetti F: Gene expression of cyclooxygenase-1 and Ca(2+)-independent phospholipase A(2) is altered in rat hippocampus during normal aging. Brain Res Bull. 2007, 73: 108-113. 10.1016/j.brainresbull.2007.02.015.PubMedCentralCrossRefPubMed
35.
Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001, 25: 402-408. 10.1006/meth.2001.1262.CrossRefPubMed
36.
Herber DL, Maloney JL, Roth LM, Freeman MJ, Morgan D, Gordon MN: Diverse microglial responses after intrahippocampal administration of lipopolysaccharide. Glia. 2006, 53: 382-391. 10.1002/glia.20272.CrossRefPubMed
37.
Planas AM, Gorina R, Chamorro A: Signalling pathways mediating inflammatory responses in brain ischaemia. Biochem Soc Trans. 2006, 34: 1267-1270. 10.1042/BST0341267.CrossRefPubMed
38.
Dembo G, Park SB, Kharasch ED: Central nervous system concentrations of cyclooxygenase-2 inhibitors in humans. Anesthesiology. 2005, 102: 409-415. 10.1097/00000542-200502000-00026.CrossRefPubMed
39.
Davies NM, McLachlan AJ, Day RO, Williams KM: Clinical pharmacokinetics and pharmacodynamics of celecoxib: a selective cyclo-oxygenase-2 inhibitor. Clin Pharmacokinet. 2000, 38: 225-242. 10.2165/00003088-200038030-00003.CrossRefPubMed
40.
Bosetti F: Arachidonic acid metabolism in brain physiology and pathology: lessons from genetically altered mouse models. J Neurochem. 2007, 102: 577-586. 10.1111/j.1471-4159.2007.04558.x.PubMedCentralCrossRefPubMed
41.
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.PubMedCentralCrossRefPubMed
42.
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.CrossRefPubMed
43.
Iadecola C, Niwa K, Nogawa S, Zhao X, Nagayama M, Araki E, Morham S, Ross ME: Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice. Proc Natl Acad Sci USA. 2001, 98: 1294-1299. 10.1073/pnas.98.3.1294.PubMedCentralCrossRefPubMed
44.
Hewett SJ, Silakova JM, Hewett JA: Oral treatment with rofecoxib reduces hippocampal excitotoxic neurodegeneration. J Pharmacol Exp Ther. 2006, 319: 1219-1224. 10.1124/jpet.106.109876.CrossRefPubMed
45.
Baik EJ, Kim EJ, Lee SH, Moon C: Cyclooxygenase-2 selective inhibitors aggravate kainic acid induced seizure and neuronal cell death in the hippocampus. Brain Res. 1999, 843: 118-129. 10.1016/S0006-8993(99)01797-7.CrossRefPubMed
46.
Tuo J, Tuaillon N, Shen D, Chan CC: Endotoxin-induced uveitis in cyclooxygenase-2-deficient mice. Invest Ophthalmol Vis Sci. 2004, 45: 2306-2313. 10.1167/iovs.03-0756.CrossRefPubMed
47.
Yin H, Cheng L, Langenbach R, Ju C: Prostaglandin I(2) and E(2) mediate the protective effects of cyclooxygenase-2 in a mouse model of immune-mediated liver injury. Hepatology. 2007, 45: 159-169. 10.1002/hep.21493.CrossRefPubMed
48.
Reilly TP, Bourdi M, Brady JN, Pise-Masison CA, Radonovich MF, George JW, Pohl LR: Expression profiling of acetaminophen liver toxicity in mice using microarray technology. Biochem Biophys Res Commun. 2001, 282: 321-328. 10.1006/bbrc.2001.4576.CrossRefPubMed
49.
Serhan CN: Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu Rev Immunol. 2007, 25: 101-137. 10.1146/annurev.immunol.25.022106.141647.CrossRefPubMed
50.
Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-Clark MJ, Willoughby DA: Inducible cyclooxygenase may have anti-inflammatory properties. Nat Med. 1999, 5: 698-701. 10.1038/9550.CrossRefPubMed
51.
Bajetto A, Bonavia R, Barbero S, Florio T, Schettini G: Chemokines and their receptors in the central nervous system. Front Neuroendocrinol. 2001, 22: 147-184. 10.1006/frne.2001.0214.CrossRefPubMed
52.
Savarin-Vuaillat C, Ransohoff RM: Chemokines and chemokine receptors in neurological disease: raise, retain, or reduce?. Neurotherapeutics. 2007, 4: 590-601. 10.1016/j.nurt.2007.07.004.CrossRefPubMed
53.
Block ML, Hong JS: Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol. 2005, 76: 77-98. 10.1016/j.pneurobio.2005.06.004.CrossRefPubMed
54.
55.
Pawate S, Shen Q, Fan F, Bhat NR: Redox regulation of glial inflammatory response to lipopolysaccharide and interferongamma. J Neurosci Res. 2004, 77: 540-551. 10.1002/jnr.20180.CrossRefPubMed
56.
Wang T, Qin L, Liu B, Liu Y, Wilson B, Eling TE, Langenbach R, Taniura S, Hong JS: Role of reactive oxygen species in LPS-induced production of prostaglandin E2 in microglia. J Neurochem. 2004, 88: 939-947. 10.1046/j.1471-4159.2003.02232.x.CrossRefPubMed
57.
58.
Naka T, Fujimoto M, Tsutsui H, Yoshimura A: Negative regulation of cytokine and TLR signalings by SOCS and others. Adv Immunol. 2005, 87: 61-122.CrossRefPubMed
59.
Bode JG, Nimmesgern A, Schmitz J, Schaper F, Schmitt M, Frisch W, Haussinger D, Heinrich PC, Graeve L: LPS and TNFalpha induce SOCS3 mRNA and inhibit IL-6-induced activation of STAT3 in macrophages. FEBS Lett. 1999, 463: 365-370. 10.1016/S0014-5793(99)01662-2.CrossRefPubMed
60.
Yadav A, Kalita A, Dhillon S, Banerjee K: JAK/STAT3 pathway is involved in survival of neurons in response to insulin-like growth factor and negatively regulated by suppressor of cytokine signaling-3. J Biol Chem. 2005, 280: 31830-31840. 10.1074/jbc.M501316200.CrossRefPubMed
61.
Breitner JC, Welsh KA, Helms MJ, Gaskell PC, Gau BA, Roses AD, Pericak-Vance MA, Saunders AM: Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiol Aging. 1995, 16: 523-530. 10.1016/0197-4580(95)00049-K.CrossRefPubMed
62.
in t' Veld BA, Ruitenberg A, Hofman A, Launer LJ, van Duijn CM, Stijnen T, Breteler MM, Stricker BH: Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med. 2001, 345: 1515-1521. 10.1056/NEJMoa010178.CrossRefPubMed
63.
Stewart WF, Kawas C, Corrada M, Metter EJ: Risk of Alzheimer's disease and duration of NSAID use. Neurology. 1997, 48: 626-632.CrossRefPubMed
64.
Aisen PS: Evaluation of selective COX-2 inhibitors for the treatment of Alzheimer's disease. J Pain Symptom Manage. 2002, 23: S35-40. 10.1016/S0885-3924(02)00374-3.CrossRefPubMed
65.
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.CrossRefPubMed
66.
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.CrossRefPubMed
67.
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.CrossRefPubMed
68.
Rogers J, Kirby LC, Hempelman SR, Berry DL, McGeer PL, Kaszniak AW, Zalinski J, Cofield M, Mansukhani L, Willson P, et al: Clinical trial of indomethacin in Alzheimer's disease. Neurology. 1993, 43: 1609-1611.CrossRefPubMed
Metadata
Title
Neuroinflammatory response to lipopolysaccharide is exacerbated in mice genetically deficient in cyclooxygenase-2
Authors
Saba Aid
Robert Langenbach
Francesca Bosetti
Publication date
01-12-2008
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2008
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-5-17

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