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

Abstract

Inflammation and the associated release of inflammatory cytokines such as tumor necrosis factor alpha (TNFalpha) may be a component of neurodegenerative 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 via binding to a specific tyrosine kinase receptor (TrkA). NGF also binds to the common neurotrophin receptor (p75(NTR)), a member of the TNFalpha 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 (NFkappaB). The similarity between p75(NTR) and TNFR-I signal transduction pathways suggests that one of the mechanisms by which TNFalpha affects neuronal survival is by impacting upon these pathways that normally promote NGF support of neurons. Here we show that arachidonic acid (AA), a signaling lipid potentially associated with TNFR-I signal cascade, induces apoptosis in PC12 cells through inhibition of both protein kinase C zeta (PKCzeta) and NFkappaB activity. We also show that apoptosis induced by AA cannot be prevented by NGF. These data support the idea that PKCzeta and NFkappaB are both essential signaling elements for mediating NGF-promoted rescue from apoptosis. Our results also suggest that AA, an inflammatory signal lipid induced by TNFalpha via binding to TNFR-I, may reduce neuronal survival by inhibiting elements of the signal cascade induced by NGF.