Cyclooxygenase-2 is a neuronal target gene of NF-kappaB.

BACKGROUND

NF-kappaB is implicated in gene regulation involved in neuronal survival, inflammmatory response and cancer. There are relatively few neuronal target genes of NF-kappaB characterized.

RESULTS

We have identified the neuronal cyclooxygenase-2 (COX-2) as a NF-kappaB target gene. In organotypic hippocampal slice cultures constitutive NF-kappaB activity was detected, which was correlated with high anti-COX-2 immunoreactivity. Aspirin a frequently used painkiller inhibits neuronal NF-kappaB activity in organotypic cultures resulting in a strong inhibition of the NF-kappaB target gene COX-2. Based on these findings, the transcriptional regulation of COX-2 by NF-kappaB was investigated. Transient transfections showed a significant increase of COX-2 promoter activity upon stimulation with PMA, an effect which could be obtained also by cotransfection of the NF-kappaB subunits p65 and p50. In the murine neuroblastoma cell line NB-4, which is characterized by constitutive NF-kappaB activity, COX-2 promoter activity could not be further increased with PMA or TNF. Constitutive promoter activity could be repressed upon cotransfection of the inhibitory subunit IkappaB-alpha. EMSA and mutational analysis conferred the regulatory NF-kappaB activity to the promoter distal kappaB-site in the human COX-2 promoter.

CONCLUSIONS

NF-kappaB regulates neuronal COX-2 gene expression, and acts as an upstream target of Aspirin. This extends Aspirin's mode of action from a covalent modification of COX-2 to the upstream regulation of COX-2 gene expression in neurons.