The p75 neurotrophin receptor (p75NTR) alters tumor necrosis factor-mediated NF-kappa B activity under physiological conditions, but direct p75NTR-mediated NF-kappa B activation requires cell stress

The p75 neurotrophin receptor (p75NTR) has been linked to activation of the NF-kappa B transcriptional complex in oligodendrocytes, Schwann cells, and PCNA cells. In this report, tumor necrosis factor (TNF)- and neurotrophin- mediated NF (nuclear factor)-kappa B activation were compared in several ce ll lines. All cell types showed TNF-mediated activation of NF-kappa B, but direct neurotrophin-dependent activation of NF-kappa B was never observed u nder normal growth conditions. In PCNA cells, a modest nerve growth factor (NGF)-dependent induction of NF-kappa B was detected but only after cells w ere subjected to severe stress, Although NGF binding did not directly activ ate NF-kappa B under normal conditions, NGF consistently altered TNF-depend ent NF-kappa B activation in each cell type examined, and extended exposure to NGF and TNF always increased NF-kappa B activation over that achieved w ith TNF alone. The increase in NF-kappa B activity mediated by NGF correlat ed with reduced levels of I kappa B alpha; NGF added alone had no effect on I kappa B alpha levels, but when added with TNF, NGF treatment significant ly reduced I kappa B alpha levels. We propose that modulation of cytokine r eceptor signaling is a significant physiological function of the p75 neurot rophin receptor and that previous reports of direct NF-kappa B activation t hrough p75NTR reflect this modulatory activity.