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.
Center for Neuronal Survival, Montreal Neurological Institute, McGill University, 3801 University Avenue, Montreal, Quebec H3A 2B4, Canada.
A L
AL
Bhakar
P P
PP
Roux
C
C
Lachance
D
D
Kryl
C
C
Zeindler
P A
PA
Barker
D006367:HeLa Cells; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology; D013314:Stress, Mechanical; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016328:NF-kappa B; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D014409:Tumor Necrosis Factor-alpha