Nerve growth factor activation of nuclear factor kappa B through its p75 receptor is an anti-apoptotic signal in RN22 schwannoma cells

Recent evidence indicates that nerve growth factor (NGF) produces its effec ts through signaling contributions from both TrkA and the p75 receptor. In contrast to its trophic actions through TrkA, NGF binding to p75 has been s hown to activate programmed cell death through a mechanism involving the st ress kinase JNK. However, this receptor also activates nuclear factor kappa B (NF-kappa B), the role of which has yet to be determined. We investigate d the function of p75-mediated NF-kappa B stimulation in regulating cell su rvival in the rat schwannoma cell line RN22, which expresses p75, but not T rkA Gel shift assays demonstrated activation of NF-kappa B in response to N GF within 30 min and lasting at least 4 h, NGF also stimulated JNK in the c ells (detected by in vitro kinase assays) with a similar time course. Preve nting activation of NF-kappa B with the specific inhibitor SN50 resulted in NGF-induced cell loss. Similarly, transfection of the cells with a mutant form of the endogenous NF-kappa B inhibitor (I kappa B alpha Delta N), whic h cannot be degraded and therefore remains bound to NF-kappa B, preventing its activation, resulted in a significant increase in the number of apoptot ic cells following NGF treatment. These results suggest that NGF activation of NF-kappa B through the p75 receptor promotes survival, counterbalancing the pro-apoptotic signal.