Down-regulation of brain nuclear factor-kappa B pathway in the cyclooxygenase-2 knockout mouse.
Cyclooxygenase (COX) is the rate-limiting enzyme in the synthesis of prostaglandins (PGs) from arachidonic acid. Evidence suggests that neuronal COX-2 gene expression is mainly regulated by the transcription factor nuclear factor kappa-B (NF-kappaB). The present study was undertaken to determine whether there is a shared regulation of NF-kappaB or of nuclear factor of activated T-cells cytoplasmic (NFATc) with COX-2 and whether these transcription factors known to regulate COX-2 expression are altered in brain from COX-2 knockout (COX-2-/-) mice compared to wild type. We found a decrease in NF-kappaB DNA-protein binding activity, which was accompanied by a reduction of the phosphorylation state of both I-kappaBalpha and p65 proteins in the COX-2-/- mice. The mRNA and protein levels of p65 were also reduced in COX-2-/- mice, whereas total cytoplasmic I-kappaB protein level was not significantly changed. Taken together, these changes may be responsible for the observed decrease in NF-kappaB DNA binding activity. NF-kappaB DNA binding activity was selectively affected in the COX-2-/- mice compared to the wild type as there was no significant change in NFATc DNA binding activity. Overall, our data indicate that constitutive brain NF-kappaB activity is decreased in COX-2 deficient mice and suggest a reciprocal coupling between NF-kappaB and COX-2.
Rao
Jagadeesh S
JS
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, 9000 Rockville Pike, Building 9, Room 1S 128, Bethesda, MD 20892, USA. jrao@mail.nih.gov
Langenbach
Robert
R
Bosetti
Francesca
F
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000172:deficiency*; D015536:Down-Regulation / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism* / Q000493:pharmacokinetics; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000502:physiology*
D016328:NF-kappa B; D021122:Protein Subunits; D012333:RNA, Messenger; D051546:Cyclooxygenase 2