Effects of tumor necrosis factor alpha on nitric oxide synthase in nerve growth factor-responding cells

Increased cytokine levels have been observed in post mortem brains of Alzheimer Disease (AD) patients accompanied by a decrease in nerve growth factor (NGF)-responsive cholinergic neurons. I report a synergistic effect of the cytokine tumor necrosis factor alpha (TNFa) and NGF on expression of nitric oxide synthase (NOS), in rat pheochromocytoma PC12 cells. NGF/TNFa-promoted iNOS can be toxic in PC12 cells. Using PC12 cell mutants lacking the low affinity p75NTR receptor, we also demonstrate that this receptor is required to mediate iNOS expression, likely acting through the transcription factor nuclear factor kappa B (NF-kB). To determine if specific regions of the brain display a selective susceptibility to TNFa enhanced iNOS expression, I investigated the effects of in vivo stereotaxic injections of recombinant rat TNFa into the fourth ventricle of adult male C57BL/6 mice. There was a robust induction of iNOS expression following the injection of TNFa, which was restricted to the basal forebrain and hippocampus. No iNOS expression was detected in the striatum, or cerebellum. Determining whether the role of TNFa is one key to the selective neurodegeneration of NGF-responsive neurons in may allow for novel therapeutic strategies.