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Molecular Pain
Published in: Molecular Pain 1/2009

Open Access 01-12-2009 | Research

Characterization of NF-kB-mediated inhibition of catechol-O-methyltransferase

Authors: Inna E Tchivileva, Andrea G Nackley, Li Qian, Sean Wentworth, Matthew Conrad, Luda B Diatchenko

Published in: Molecular Pain | Issue 1/2009

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Abstract

Background

Catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, has recently been implicated in the modulation of pain. Specifically, low COMT activity is associated with heightened pain perception and development of musculoskeletal pain in humans as well as increased experimental pain sensitivity in rodents.

Results

We report that the proinflammatory cytokine tumor necrosis factor α (TNFα) downregulates COMT mRNA and protein in astrocytes. Examination of the distal COMT promoter (P2-COMT) reveals a putative binding site for nuclear factor κB (NF-κB), the pivotal regulator of inflammation and the target of TNFα. Cell culture assays and functional deletion analyses of the cloned P2-COMT promoter demonstrate that TNFα inhibits P2-COMT activity in astrocytes by inducing NF-κB complex recruitment to the specific κB binding site.

Conclusion

Collectively, our findings provide the first evidence for NF-κB-mediated inhibition of COMT expression in the central nervous system, suggesting that COMT contributes to the pathogenesis of inflammatory pain states.
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Literature
1.
Axelrod J, Tomchik R: O-methylation of catechol amines in vivo. J Biol Chem 1958, 233: 702–705.PubMed
2.
Mannisto PT, Kaakkola S: Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev 1999, 51: 593–628.PubMed
3.
Zhu BT: Catechol-O-Methyltransferase (COMT)-mediated methylation metabolism of endogenous bioactive catechols and modulation by endobiotics and xenobiotics: importance in pathophysiology and pathogenesis. Curr Drug Metab 2002, 3: 321–349. 10.2174/1389200023337586PubMedCrossRef
4.
Tunbridge EM, Harrison PJ, Weinberger DR: Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol Psychiatry 2006, 60: 141–151. 10.1016/j.biopsych.2005.10.024PubMedCrossRef
5.
Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D, et al.: Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet 2005, 14: 135–143. 10.1093/hmg/ddi013PubMedCrossRef
6.
Diatchenko L, Nackley AG, Slade GD, Bhalang K, Belfer I, Max MB, Goldman D, Maixner W: Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli. Pain 2006, 125: 216–224. 10.1016/j.pain.2006.05.024PubMedCrossRef
7.
Marbach JJ, Levitt M: Erythrocyte catechol-O-methyltransferase activity in facial pain patients. J Dent Res 1976, 55: 711.PubMedCrossRef
8.
Nackley AG, Tan KS, Fecho K, Flood P, Diatchenko L, Maixner W: Catechol-O-methyltransferase inhibition increases pain sensitivity through activation of both beta2- and beta3-adrenergic receptors. Pain 2007, 128: 199–208. 10.1016/j.pain.2006.09.022PubMedCrossRef
9.
Salminen M, Lundstrom K, Tilgmann C, Savolainen R, Kalkkinen N, Ulmanen I: Molecular cloning and characterization of rat liver catechol-O-methyltransferase. Gene 1990, 93: 241–247. 10.1016/0378-1119(90)90231-FPubMedCrossRef
10.
Lundstrom K, Salminen M, Jalanko A, Savolainen R, Ulmanen I: Cloning and characterization of human placental catechol-O-methyltransferase cDNA. DNA Cell Biol 1991, 10: 181–189. 10.1089/dna.1991.10.181PubMedCrossRef
11.
Tenhunen J, Salminen M, Lundstrom K, Kiviluoto T, Savolainen R, Ulmanen I: Genomic organization of the human catechol O-methyltransferase gene and its expression from two distinct promoters. Eur J Biochem 1994, 223: 1049–1059. 10.1111/j.1432-1033.1994.tb19083.xPubMedCrossRef
12.
Hong J, Shu-Leong H, Tao X, Lap-Ping Y: Distribution of catechol-O-methyltransferase expression in human central nervous system. Neuroreport 1998, 9: 2861–2864.PubMedCrossRef
13.
Tenhunen J, Salminen M, Jalanko A, Ukkonen S, Ulmanen I: Structure of the rat catechol-O-methyltransferase gene: separate promoters are used to produce mRNAs for soluble and membrane-bound forms of the enzyme. DNA Cell Biol 1993, 12: 253–263. 10.1089/dna.1993.12.253PubMedCrossRef
14.
Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I, Taskinen J: Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 1995, 34: 4202–4210. 10.1021/bi00013a008PubMedCrossRef
15.
16.
Matsumoto M, Weickert CS, Akil M, Lipska BK, Hyde TM, Herman MM, Kleinman JE, Weinberger DR: Catechol O-methyltransferase mRNA expression in human and rat brain: evidence for a role in cortical neuronal function. Neuroscience 2003, 116: 127–137. 10.1016/S0306-4522(02)00556-0PubMedCrossRef
17.
Karhunen T, Tilgmann C, Ulmanen I, Panula P: Catechol-O-methyltransferase (COMT) in rat brain: immunoelectron microscopic study with an antiserum against rat recombinant COMT protein. Neurosci Lett 1995, 187: 57–60. 10.1016/0304-3940(95)11337-VPubMedCrossRef
18.
Lundstrom K, Tenhunen J, Tilgmann C, Karhunen T, Panula P, Ulmanen I: Cloning, expression and structure of catechol-O-methyltransferase. Biochim Biophys Acta 1995, 1251: 1–10.PubMedCrossRef
19.
Kaplan GP, Hartman BK, Creveling CR: Immunohistochemical demonstration of catechol-o-methyltransferase in mammalian brain. Brain Res 1979, 167: 241–250. 10.1016/0006-8993(79)90819-9PubMedCrossRef
20.
Sommer C, Kress M: Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci Lett 2004, 361: 184–187. 10.1016/j.neulet.2003.12.007PubMedCrossRef
21.
Wieseler-Frank J, Maier SF, Watkins LR: Central proinflammatory cytokines and pain enhancement. Neurosignals 2005, 14: 166–174. 10.1159/000087655PubMedCrossRef
22.
De Leo JA, Tawfik VL, LaCroix-Fralish ML: The tetrapartite synapse: path to CNS sensitization and chronic pain. Pain 2006, 122: 17–21. 10.1016/j.pain.2006.02.034PubMedCrossRef
23.
McMahon SB, Cafferty WB, Marchand F: Immune and glial cell factors as pain mediators and modulators. Exp Neurol 2005, 192: 444–462. 10.1016/j.expneurol.2004.11.001PubMedCrossRef
24.
Guo W, Wang H, Watanabe M, Shimizu K, Zou S, LaGraize SC, Wei F, Dubner R, Ren K: Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci 2007, 27: 6006–6018. 10.1523/JNEUROSCI.0176-07.2007PubMedCentralPubMedCrossRef
25.
Raghavendra V, Tanga FY, DeLeo JA: Complete Freunds adjuvant-induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the CNS. Eur J Neurosci 2004, 20: 467–473. 10.1111/j.1460-9568.2004.03514.xPubMedCrossRef
26.
Wei XH, Zang Y, Wu CY, Xu JT, Xin WJ, Liu XG: Peri-sciatic administration of recombinant rat TNF-alpha induces mechanical allodynia via upregulation of TNF-alpha in dorsal root ganglia and in spinal dorsal horn: the role of NF-kappa B pathway. Exp Neurol 2007, 205: 471–484. 10.1016/j.expneurol.2007.03.012PubMedCrossRef
27.
Shafer DM, Assael L, White LB, Rossomando EF: Tumor necrosis factor-alpha as a biochemical marker of pain and outcome in temporomandibular joints with internal derangements. J Oral Maxillofac Surg 1994, 52: 786–791. discussion 791–782 10.1016/0278-2391(94)90217-8PubMedCrossRef
28.
Tak PP, Smeets TJ, Daha MR, Kluin PM, Meijers KA, Brand R, Meinders AE, Breedveld FC: Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity. Arthritis Rheum 1997, 40: 217–225. 10.1002/art.1780400206PubMedCrossRef
29.
Lindenlaub T, Sommer C: Cytokines in sural nerve biopsies from inflammatory and non-inflammatory neuropathies. Acta Neuropathol 2003, 105: 593–602.PubMed
30.
Aggarwal BB: Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 2003, 3: 745–756. 10.1038/nri1184PubMedCrossRef
31.
Chen G, Goeddel DV: TNF-R1 signaling: a beautiful pathway. Science 2002, 296: 1634–1635. 10.1126/science.1071924PubMedCrossRef
32.
Makarov SS: NF-kappaB as a therapeutic target in chronic inflammation: recent advances. Mol Med Today 2000, 6: 441–448. 10.1016/S1357-4310(00)01814-1PubMedCrossRef
33.
O'Neill LA, Kaltschmidt C: NF-kappa B: a crucial transcription factor for glial and neuronal cell function. Trends Neurosci 1997, 20: 252–258. 10.1016/S0166-2236(96)01035-1PubMedCrossRef
34.
35.
Kaltschmidt B, Widera D, Kaltschmidt C: Signaling via NF-kappaB in the nervous system. Biochim Biophys Acta 2005, 1745: 287–299. 10.1016/j.bbamcr.2005.05.009PubMedCrossRef
36.
Yamamoto Y, Gaynor RB: IkappaB kinases: key regulators of the NF-kappaB pathway. Trends Biochem Sci 2004, 29: 72–79. 10.1016/j.tibs.2003.12.003PubMedCrossRef
37.
Ghosh S, Karin M: Missing pieces in the NF-kappaB puzzle. Cell 2002,109(Suppl):S81–96. 10.1016/S0092-8674(02)00703-1PubMedCrossRef
38.
Chan CF, Sun WZ, Lin JK, Lin-Shiau SY: Activation of transcription factors of nuclear factor kappa B, activator protein-1 and octamer factors in hyperalgesia. Eur J Pharmacol 2000, 402: 61–68. 10.1016/S0014-2999(00)00431-3PubMedCrossRef
39.
Lee KM, Kang BS, Lee HL, Son SJ, Hwang SH, Kim DS, Park JS, Cho HJ: Spinal NF-kB activation induces COX-2 upregulation and contributes to inflammatory pain hypersensitivity. Eur J Neurosci 2004, 19: 3375–3381. 10.1111/j.0953-816X.2004.03441.xPubMedCrossRef
40.
Ma W, Bisby MA: Increased activation of nuclear factor kappa B in rat lumbar dorsal root ganglion neurons following partial sciatic nerve injuries. Brain Res 1998, 797: 243–254. 10.1016/S0006-8993(98)00380-1PubMedCrossRef
41.
Madrigal JL, Moro MA, Lizasoain I, Lorenzo P, Castrillo A, Bosca L, Leza JC: Inducible nitric oxide synthase expression in brain cortex after acute restraint stress is regulated by nuclear factor kappaB-mediated mechanisms. J Neurochem 2001, 76: 532–538. 10.1046/j.1471-4159.2001.00108.xPubMedCrossRef
42.
Wu LC, Goettl VM, Madiai F, Hackshaw KV, Hussain SR: Reciprocal regulation of nuclear factor kappa B and its inhibitor ZAS3 after peripheral nerve injury. BMC Neurosci 2006, 7: 4. 10.1186/1471-2202-7-4PubMedCentralPubMedCrossRef
43.
Tegeder I, Niederberger E, Schmidt R, Kunz S, Guhring H, Ritzeler O, Michaelis M, Geisslinger G: Specific Inhibition of IkappaB kinase reduces hyperalgesia in inflammatory and neuropathic pain models in rats. J Neurosci 2004, 24: 1637–1645. 10.1523/JNEUROSCI.3118-03.2004PubMedCrossRef
44.
Laughlin TM, Bethea JR, Yezierski RP, Wilcox GL: Cytokine involvement in dynorphin-induced allodynia. Pain 2000, 84: 159–167. 10.1016/S0304-3959(99)00195-5PubMedCrossRef
45.
Meunier A, Latremoliere A, Dominguez E, Mauborgne A, Philippe S, Hamon M, Mallet J, Benoliel JJ, Pohl M: Lentiviral-mediated targeted NF-kappaB blockade in dorsal spinal cord glia attenuates sciatic nerve injury-induced neuropathic pain in the rat. Mol Ther 2007, 15: 687–697.PubMed
46.
Brambilla R, Bracchi-Ricard V, Hu WH, Frydel B, Bramwell A, Karmally S, Green EJ, Bethea JR: Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury. J Exp Med 2005, 202: 145–156. 10.1084/jem.20041918PubMedCentralPubMedCrossRef
47.
Fu ES, Zhang YP, Sagen J, Yang ZQ, Bethea JR: Transgenic glial nuclear factor-kappa B inhibition decreases formalin pain in mice. Neuroreport 2007, 18: 713–717. 10.1097/WNR.0b013e3280d9e869PubMedCrossRef
48.
Igwe OJ: Modulation of peripheral inflammation in sensory ganglia by nuclear factor (kappa)B decoy oligodeoxynucleotide: involvement of SRC kinase pathway. Neurosci Lett 2005, 381: 114–119. 10.1016/j.neulet.2005.02.020PubMedCrossRef
49.
Brown K, Park S, Kanno T, Franzoso G, Siebenlist U: Mutual regulation of the transcriptional activator NF-kappa B and its inhibitor, I kappa B-alpha. Proc Natl Acad Sci USA 1993, 90: 2532–2536. 10.1073/pnas.90.6.2532PubMedCentralPubMedCrossRef
50.
Xie T, Ho SL, Ramsden D: Characterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcription. Mol Pharmacol 1999, 56: 31–38.PubMed
51.
Heinemeyer T, Wingender E, Reuter I, Hermjakob H, Kel AE, Kel OV, Ignatieva EV, Ananko EA, Podkolodnaya OA, Kolpakov FA, et al.: Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL. Nucleic Acids Res 1998, 26: 362–367. 10.1093/nar/26.1.362PubMedCentralPubMedCrossRef
52.
Varfolomeev EE, Ashkenazi A: Tumor necrosis factor: an apoptosis JuNKie? Cell 2004, 116: 491–497. 10.1016/S0092-8674(04)00166-7PubMedCrossRef
53.
Sitcheran R, Gupta P, Fisher PB, Baldwin AS: Positive and negative regulation of EAAT2 by NF-kappaB: a role for N-myc in TNFalpha-controlled repression. Embo J 2005, 24: 510–520. 10.1038/sj.emboj.7600555PubMedCentralPubMedCrossRef
54.
Shen Z, Peedikayil J, Olson GK, Siebert PD, Fang Y: Multiple transcription factor profiling by enzyme-linked immunoassay. Biotechniques 2002, 32: 1168.PubMed
55.
Jiang H, Xie T, Ramsden DB, Ho SL: Human catechol-O-methyltransferase down-regulation by estradiol. Neuropharmacology 2003, 45: 1011–1018. 10.1016/S0028-3908(03)00286-7PubMedCrossRef
56.
Sasaki M, Kaneuchi M, Sakuragi N, Dahiya R: Multiple promoters of catechol-O-methyltransferase gene are selectively inactivated by CpG hypermethylation in endometrial cancer. Cancer Res 2003, 63: 3101–3106.PubMed
57.
Abdolmaleky HM, Cheng KH, Faraone SV, Wilcox M, Glatt SJ, Gao F, Smith CL, Shafa R, Aeali B, Carnevale J, et al.: Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. Hum Mol Genet 2006, 15: 3132–3145. 10.1093/hmg/ddl253PubMedCentralPubMedCrossRef
58.
Belvin MP, Anderson KV: A conserved signaling pathway: the Drosophila toll-dorsal pathway. Annu Rev Cell Dev Biol 1996, 12: 393–416. 10.1146/annurev.cellbio.12.1.393PubMedCrossRef
59.
Cinar B, Yeung F, Konaka H, Mayo MW, Freeman MR, Zhau HE, Chung LW: Identification of a negative regulatory cis-element in the enhancer core region of the prostate-specific antigen promoter: implications for intersection of androgen receptor and nuclear factor-kappaB signalling in prostate cancer cells. Biochem J 2004, 379: 421–431. 10.1042/BJ20031661PubMedCentralPubMedCrossRef
60.
Ke S, Rabson AB, Germino JF, Gallo MA, Tian Y: Mechanism of suppression of cytochrome P-450 1A1 expression by tumor necrosis factor-alpha and lipopolysaccharide. J Biol Chem 2001, 276: 39638–39644. 10.1074/jbc.M106286200PubMedCrossRef
61.
Garrison CJ, Dougherty PM, Carlton SM: GFAP expression in lumbar spinal cord of naive and neuropathic rats treated with MK-801. Exp Neurol 1994, 129: 237–243. 10.1006/exnr.1994.1165PubMedCrossRef
62.
Ledeboer A, Gamanos M, Lai W, Martin D, Maier SF, Watkins LR, Quan N: Involvement of spinal cord nuclear factor kappaB activation in rat models of proinflammatory cytokine-mediated pain facilitation. Eur J Neurosci 2005, 22: 1977–1986. 10.1111/j.1460-9568.2005.04379.xPubMedCrossRef
63.
Dunn SL, Young EA, Hall MD, McNulty S: Activation of astrocyte intracellular signaling pathways by interleukin-1 in rat primary striatal cultures. Glia 2002, 37: 31–42. 10.1002/glia.10010PubMedCrossRef
64.
Srinivasan D, Yen JH, Joseph DJ, Friedman W: Cell type-specific interleukin-1beta signaling in the CNS. J Neurosci 2004, 24: 6482–6488. 10.1523/JNEUROSCI.5712-03.2004PubMedCrossRef
65.
Milligan ED, Twining C, Chacur M, Biedenkapp J, O'Connor K, Poole S, Tracey K, Martin D, Maier SF, Watkins LR: Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci 2003, 23: 1026–1040.PubMed
66.
Roman-Blas JA, Jimenez SA: NF-kappaB as a potential therapeutic target in osteoarthritis and rheumatoid arthritis. Osteoarthritis Cartilage 2006, 14: 839–848. 10.1016/j.joca.2006.04.008PubMedCrossRef
67.
Schaible HG, Schmelz M, Tegeder I: Pathophysiology and treatment of pain in joint disease. Adv Drug Deliv Rev 2006, 58: 323–342. 10.1016/j.addr.2006.01.011PubMedCrossRef
68.
Liu B, Du L, Kong LY, Hudson PM, Wilson BC, Chang RC, Abel HH, Hong JS: Reduction by naloxone of lipopolysaccharide-induced neurotoxicity in mouse cortical neuron-glia co-cultures. Neuroscience 2000, 97: 749–756. 10.1016/S0306-4522(00)00057-9PubMedCrossRef
Metadata
Title
Characterization of NF-kB-mediated inhibition of catechol-O-methyltransferase
Authors
Inna E Tchivileva
Andrea G Nackley
Li Qian
Sean Wentworth
Matthew Conrad
Luda B Diatchenko
Publication date
01-12-2009
Publisher
BioMed Central
Published in
Molecular Pain / Issue 1/2009
Electronic ISSN: 1744-8069
DOI
https://doi.org/10.1186/1744-8069-5-13

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