NGF-resistant PC12 cell death induced by arachidonic acid is accompanied by a decrease of active PKC zeta and nuclear factor kappa B

Inflammation and the associated release of inflammatory cytokines such as t umor necrosis factor alpha (TNF alpha) may be a component of neurodegenerat ive diseases associated with aging or chronic HIV-1 infection. Most of the neurons that are affected under these conditions require a constant supply of trophic factors such as nerve growth factor (NGF) for survival. NGF acts cia binding to a specific tyrosine kinase receptor (TrkA), NGF also binds to the common neurotrophin receptor (p75(NTR)), a member of the TNF alpha. receptor (TNFR-I) superfamily, whose function may be to modulate apoptosis via the release of ceramide and the activation of the transcription factor nuclear factor kappa B (NF kappa B), The similarity between p75(NTR) and TN FR-I signal transduction pathways suggests that one of the mechanisms by wh ich TNF alpha affects neuronal survival is by impacting upon these pathways that normally promote NGF support of neurons. Here we show that arachidoni c acid (AA), a signaling lipid potentially associated with TNFR-I signal ca scade, induces apoptosis in PC12 cells through inhibition of both protein k inase C zeta (PKC zeta) and NF kappa B activity. We also show that apoptosi s induced by AA cannot be prevented by NGF, These data support the idea tha t PKC zeta and NF kappa B are both essential signaling elements for mediati ng NGF-promoted rescue from apoptosis, Our results also suggest that AA, an inflammatory signal lipid induced by TNF alpha via binding to TNFR-I, may reduce neuronal survival by inhibiting elements of the signal cascade induc ed by NGF, J, Neurosci, Res. 57:219-226, 1999, (C) 1999 Wiley-Liss, Inc.