Down-regulation of brain nuclear factor-kappa B pathway in the cyclooxygenase-2 knockout mouse

Abstract

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-κB). The present study was undertaken to determine whether there is a shared regulation of NF-κB 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-κB DNA–protein binding activity, which was accompanied by a reduction of the phosphorylation state of both I-κBα 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-κB protein level was not significantly changed. Taken together, these changes may be responsible for the observed decrease in NF-κB DNA binding activity. NF-κB 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-κB activity is decreased in COX-2 deficient mice and suggest a reciprocal coupling between NF-κB and COX-2.