Leukemia inhibitory factor requires concurrent p75(LNTR) signaling to induce apoptosis of cultured sympathetic neurons

Apoptosis may result either from positive induction by ligand binding to a plasma membrane receptor or from negative induction attributable to loss of a suppressor signal. For example, apoptosis of developing sympathetic neur ons may be induced in culture either by exposure to leukemia inhibitory fac tor (LIF) or by deprivation of nerve growth factor. This study compared the cell death pathways activated in sympathetic neurons by these two differen t stimuli. Both types of cell death were developmentally regulated; both we re maximal in the immediate postnatal period and disappeared over the next 2 weeks. Both types of cell death were reduced by genetic deletion of Bax o r by virally mediated overexpression of Bcl-2. Similarly both were reduced by inhibition of caspase activity or by inhibition of Nedd-2 synthesis with antisense oligonucleotides. Finally, both involved activation of c-Jun N-t erminal kinase (JNK) signaling. Nedd-2 expression by sympathetic neurons de clined in parallel with the developmental loss of LIF-mediated cell death, suggesting that downregulation of the caspase during development may underl ie the loss of cytokine-mediated apoptosis. Treatment of sympathetic neuron s with an antibody that blocks the function of the low-affinity neurotrophi n receptor (p75(LNTR)) prevented LIF-induced cell death. Similarly genetic deletion of p75(LNTR) prevented apoptosis after LIF treatment. These observ ations suggest that concurrent p75(LNTR) signaling is necessary for LIF-ind uced cell death and that cytokine-mediated cell death and growth factor dep rivation appear to activate the same intracellular pathways involving JNK s ignaling.