NFκB Activates in vivo the Synthesis of Inducible Cox-2 in the Brain

Publisher Website
Google Scholar
Abstract
Interleukin-1 (IL-1) induces cyclooxygenase-2 (Cox-2) expression in many of its cellular targets resulting in production and release of prostaglandins. Although IL-1-induced Cox-2 expression most likely requires activation of nuclear transcription factor kappa B (NFB) pathway, this has never been formally demonstrated in vivo. We tested this using a specific inhibitor of NFB activation, the NEMO binding domain (NBD) peptide, that has been shown previously to be effective in various in vivo models of acute inflammation. Incubation of rat glioma cells with the NBD peptide blocked IL-1-induced NFB nuclear translocation. Furthermore, after injection of a biotinylated version of the NBD peptide into the lateral ventricle of the brain, we found that it readily diffused to its potential cellular targets in vivo. To test the effects of the peptide on NFB activation and Cox-2 expression in the brain, we injected it intracerebroventricularly (36 g/rat) into rats before intraperitoneal injection of IL-1 (60 g/kg). Treatment with NBD peptide completely abolished IL-1-induced NFB activation and Cox-2 synthesis in microvasculature. In contrast, the peptide had no effect on constitutive neuronal Cox-2. These findings strongly support the hypothesis that IL-1-induced NFB activation plays a major role in transmission of immune signals from the periphery to the brain.