Tumor necrosis factor alpha regulates responses to nerve growth factor, promoting neural cell survival but suppressing differentiation of neuroblastoma cells.

Although nerve growth factor (NGF) promotes survival of neurons, tumor necrosis factor alpha (TNF-alpha) contributes to cell death triggered by NGF depletion, through TNF-alpha receptor (TNFR) 1. In contrast to this effect, TNF-alpha can promote neural cell survival via TNF-alpha receptor TNFR2. Although these findings demonstrate pivotal roles of TNF-alpha and NGF in cell fate decisions, cross-talk between these signaling pathways has not been clarified. We find that NGF can induce TNF-alpha synthesis through the nuclear factor-kappaB transcription factor. This provides a new basis for examining the cross-talk between NGF and TNF-alpha. Inhibition of TNFR2 shows opposite effects on two downstream kinases of NGF, extracellular signal-regulated kinase (Erk) and Akt. It increases Erk activation by NGF, and this increased activation induces differentiation of neuroblastoma cell lines. Reciprocally, inhibition of TNFR2 decreases Akt activation by NGF. Consistent with an essential role of Akt in survival signaling, inhibition of TNF-alpha signaling decreases NGF-dependent survival of neurons from rat dorsal root ganglia. Thus, NGF and NGF-induced TNF-alpha cooperate to activate Akt, promoting survival of normal neural cells. However, the NGF-induced TNF-alpha suppresses Erk activation by NGF, blocking NGF-induced differentiation of neuroblastoma cells. TNFR2 signaling could be a novel target to modulate cell responses to NGF.