Characterization of NF-kB-mediated inhibition of catechol-O-methyltransferase.
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.
Tchivileva
Inna E
IE
Center for Neurosensory Disorders, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599-7455, USA. tchivilei@dentistry.unc.edu
Nackley
Andrea G
AG
Qian
Li
L
Wentworth
Sean
S
Conrad
Matthew
M
Diatchenko
Luda B
LB
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
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