Cyclooxygenase-2 is a neuronal target gene of NF-κB

We have identified the neuronal cyclooxygenase-2 (COX-2) as a NF-κB target gene. In organotypic hippocampal slice cultures constitutive NF-κB activity was detected, which was correlated with high anti-COX-2 immunoreactivity. Aspirin a frequently used painkiller inhibits neuronal NF-κB activity in organotypic cultures resulting in a strong inhibition of the NF-κB target gene COX-2. Based on these findings, the transcriptional regulation of COX-2 by NF-κB 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-κB subunits p65 and p50. In the murine neuroblastoma cell line NB-4, which is characterized by constitutive NF-κB 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 IκB-α. EMSA and mutational analysis conferred the regulatory NF-κB activity to the promoter distal κB-site in the human COX-2 promoter.NF-κB 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.NF-κB a transcription factor with inducible activity, present in most cell types. This factor is crucially involved in regulation of genes relevant in neuronal survival, inflammmatory response, cancer and innate immunity [1,2]. The activation of NF-κB is mainly controlled at the posttranscriptional level by complex formation with the inhibitory subunit IκB in the cytoplasm [3]. Phosphorylation of IκB prior to degradation is catalyzed by the activation of a complex consisting of two kinases (IKK-α and IKK-β) [4] together with a modifying subunit called NEMO [5] or IKK-γ [6]. Binding of NEMO is important to mediate the cytokine response in a aktivation of the kinases [7]. Recently it w