Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-methyl-D-aspartate receptor activation -: Essential role of a TNF receptor 2-mediated phosphatidylinositol 3-kinase-dependent NF-κB pathway

We have previously shown that two tumor necrosis factor (TNF) receptors (TNFR) exhibit antagonistic functions during neurodegenerative processes in vivo with TNFR1 aggravating and TNFR2 reducing neuronal cell loss, respectively. To elucidate the neuroprotective signaling pathways of TNFR2, we investigated glutamate-induced excitotoxicity in primary cortical neurons. TNF-expressing neurons from TNF-transgenic mice were found to be strongly protected from glutamate-induced apoptosis. Neurons from wild type and TNFR1(-/-) mice prestimulated with TNF or agonistic TNFR2-specific antibodies were also resistant to excitotoxicity, whereas TNFR2(-/-) neurons died upon glutamate and/or TNF exposures. Both protein kinase B/Akt and nuclear factor-kappaB (NF-kappaB) activation were apparent upon TNF treatment. Both TNFR1 and TNFR2 induced the NF-kappaB pathway, yet with distinguishable kinetics and upstream activating components, TNFR1 only induced transient NF-kappaB activation, whereas TNFR2 facilitated long term phosphatidylinositol 3-kinase-dependent NF-kappaB activation strictly. Glutamate-induced triggering of the ionotropic N-methyl-D-aspartate receptor was required for the enhanced and persistent phosphatidylinositol 3-kinase-dependent NF-kappaB activation by TNFR2, indicating a positive cooperation of TNF and neurotransmitter-induced signal pathways. TNFR2-induced persistent NF-kappaB activity was essential for neuronal survival. Thus, the duration of NF-kappaB activation is a critical determinant for sensitivity toward excitotoxic stress and is dependent on a differential upstream signal pathway usage of the two TNFRs.