Tumour necrosis factor-alpha- vs. growth factor deprivation-promoted cell death: different receptor requirements for mediating nerve growth factor-promoted rescue.
Physiological and pathological aging of the central nervous system (CNS) is characterized by functional neuronal impairments which may lead to perturbed cell homeostasis and eventually to neuronal death. Many toxic events may underlie age-related neurodegeneration. These include the effects of beta amyloid, Tau and mutated presenilin proteins, free radicals and oxidative stress, pro-inflammatory cytokines and lack of growth factor support, which can be individually or collectively involved. Taken individually, these toxicants can induce very diverse cell responses, thus requiring individually targeted corrective interventions upstream of common cell death (apoptotic) pathways. Recent preliminary evidence suggests that the pro-inflammatory cytokine tumour necrosis factor alpha (TNFalpha) and growth factor withdrawal can both activate a common apoptotic pathway in nerve growth factor (NGF)-responsive PC12 cells involving caspase 3, albeit through very distinct upstream pathways: the former through active signalling and the latter through passive or lack of survival signalling. Here, we show that NGF can rescue PC12 cells from both growth factor withdrawal- and TNFalpha-promoted cell death. However, NGF rescue from growth factor withdrawal requires NGF signalling through the high-affinity tyrosine kinase receptor (TrkA), while NGF rescue from TNFalpha-promoted cell death requires NGF signalling through the low-affinity p75NTR receptor. These results strengthen the idea that prevention of age- or pathology-associated neurodegeneration may require varied molecular approaches reflecting the diversity of the toxicants involved, possibly acting simultaneously.
Pappas
Todd C
TC
Center for Biomedical Engineering, The University of Texas Medical Branch at Galveston, Galveston, TX 77555 -1043, USA.
Decorti
Francesco
F
Macdonald
Nancy J
NJ
Neet
Kenneth E
KE
Taglialatela
Giulio
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003470:Culture Media; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009363:Neoplasm Proteins / Q000187:drug effects / Q000502:physiology; D020932:Nerve Growth Factor / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects / Q000648:ultrastructure; D016716:PC12 Cells / Q000166:cytology / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA / Q000187:drug effects / Q000502:physiology; D017475:Receptors, Nerve Growth Factor / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D003470:Culture Media; D009363:Neoplasm Proteins; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D014409:Tumor Necrosis Factor-alpha; D020932:Nerve Growth Factor; D020917:Receptor, trkA