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

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