title: Characterization of NF-kB-mediated inhibition of catechol-O-methyltransferase.
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 alpha (TNFalpha) downregulates COMT mRNA and protein in astrocytes. Examination of the distal COMT promoter (P2-COMT) reveals a putative binding site for nuclear factor kappaB (NF-kappaB), the pivotal regulator of inflammation and the target of TNFalpha. Cell culture assays and functional deletion analyses of the cloned P2-COMT promoter demonstrate that TNFalpha inhibits P2-COMT activity in astrocytes by inducing NF-kappaB complex recruitment to the specific kappaB binding site.
  
  
  CONCLUSIONS
  Collectively, our findings provide the first evidence for NF-kappaB-mediated inhibition of COMT expression in the central nervous system, suggesting that COMT contributes to the pathogenesis of inflammatory pain states.
authors.affiliation: Center for Neurosensory Disorders, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599-7455, USA. tchivilei@dentistry.unc.edu
authors.forename: Inna E
authors.initials: IE
authors.lastname: Tchivileva
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Nackley
authors.forename: Li
authors.initials: L
authors.lastname: Qian
authors.forename: Sean
authors.initials: S
authors.lastname: Wentworth
authors.forename: Matthew
authors.initials: M
authors.lastname: Conrad
authors.forename: Luda B
authors.initials: LB
authors.lastname: Diatchenko
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology; D001665:Binding Sites; D002394:Catechol O-Methyltransferase / Q000235:genetics; D065098:Catechol O-Methyltransferase Inhibitors; D002478:Cells, Cultured; D003001:Cloning, Molecular; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D065098:Catechol O-Methyltransferase Inhibitors; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606206:Nfkbia protein, rat; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D002394:Catechol O-Methyltransferase