The p75 Neurotrophin Receptor (p75NTR) Alters Tumor Necrosis Factor-mediated NF-κB Activity under Physiological Conditions, but Direct p75NTR-mediated NF-κB Activation Requires Cell Stress

Abstract The p75 neurotrophin receptor (p75NTR) has been linked to activation of the NF-κB transcriptional complex in oligodendrocytes, Schwann cells, and PCNA cells. In this report, tumor necrosis factor (TNF)- and neurotrophin-mediated NF (nuclear factor)-κB activation were compared in several cell lines. All cell types showed TNF-mediated activation of NF-κB, but direct neurotrophin-dependent activation of NF-κB was never observed under normal growth conditions. In PCNA cells, a modest nerve growth factor (NGF)-dependent induction of NF-κB was detected but only after cells were subjected to severe stress. Although NGF binding did not directly activate NF-κB under normal conditions, NGF consistently altered TNF-dependent NF-κB activation in each cell type examined, and extended exposure to NGF and TNF always increased NF-κB activation over that achieved with TNF alone. The increase in NF-κB activity mediated by NGF correlated with reduced levels of IκBα; NGF added alone had no effect on IκBα levels, but when added with TNF, NGF treatment significantly reduced IκBα levels. We propose that modulation of cytokine receptor signaling is a significant physiological function of the p75 neurotrophin receptor and that previous reports of direct NF-κB activation through p75NTR reflect this modulatory activity.