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

Mol Pain. 2009 Mar 16:5:13. doi: 10.1186/1744-8069-5-13.

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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Astrocytes / drug effects
  • Astrocytes / enzymology
  • Binding Sites
  • Catechol O-Methyltransferase / genetics
  • Catechol O-Methyltransferase Inhibitors*
  • Cells, Cultured
  • Cloning, Molecular
  • Down-Regulation / drug effects
  • Humans
  • I-kappa B Proteins / metabolism
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Promoter Regions, Genetic / genetics
  • Rats
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Catechol O-Methyltransferase Inhibitors
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, rat
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Catechol O-Methyltransferase