NF-kB control of neuronal apoptosis in Alzheimer disease

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During FY12 we accomplished the following: 1. Determined that 3 out of 5 COX-2 inhibitors suppressed c-Rel activation in CD4+ T cells. All those that inhibited Rel also prevented up-regulation of several Rel-responsive TNF and TNF-R super family members that we previously identified as targets of celecoxib. 2. We found that celecoxib inhibited differentiation to inflammatory TH17 cells in vitro This was not due to suppression of the lineage-determining transcription factor RORϒ-T. 3. Using celecoxib at different doses we found that maximal suppression of Rel coincided with activation of ER stress. Earlier studies have indicated that ER stress leads to up-regulation of NF-κB. Our observations provide a novel connection between ER stress and down-regulation of a specific NF-κB family member. A manuscript describing these findings is currently under revision.