Tumour necrosis factor-alpha- vs. growth factor deprivation-promoted cell death: distinct converging pathways.
Perturbations of neuronal physiological homeostasis are likely to underscore neuronal demise/impairments that are reportedly associated with aging of the central nervous system and age-related neurodegenerative diseases such as Alzheimer's disease (AD). A number of age- and/or disease-associated neurotoxic events has been described. These include abnormally modified proteins such as beta amyloid and hyper-phosphorylated Tau, cytokines such as tumour necrosis factor-alpha (TNFalpha), high levels of free radicals conducive to oxidative stress, and impaired/decreased neuronal trophic support by neurotrophic factors. Overall, it could be argued that toxic events in the aged brain are either active, such as those due to a direct action of cytokines, or passive, such as those due to lack of growth factor support. It is therefore conceivable that cellular responses to such diverse toxic stimuli are different, suggesting that interventions should be targeted accordingly. In order to begin answering this question, we determined in PC12 cells the time course of activity, in response to TNFalpha (active) or growth factor withdrawal (passive), of protein kinase c-zeta (PKCzeta), nuclear factor kappa B (NFkappaB), caspases 3 and 8, and poly (ADP-ribose) polymerase (PARP), key signal transduction elements associated with modulation of cell death/survival in PC12 cells. We found that the overall activity of PKCzeta, NFkappaB and caspase 8 was significantly different depending on the apoptotic initiator. The pattern of caspase 3 and PARP activity, however, was not statistically different between serum-free- and TNFalpha-induced cell death conditions. This suggests that two distinct cell responses are elicited that converge at caspase 3, which then induces downstream events involved in the execution of a common apoptotic programme. These results contribute to the aim of differentially targeting neuronal death in the aged brain (characterized by neurotrophic factor impairments) or in the diseased brain (e.g. AD, characterized by elevated levels of pro-inflammatory cytokines).
Macdonald
Nancy J
NJ
Marine Biomedical Institute-Department of Anatomy & Neurosciences, The University of Texas Medical Branch at Galveston, Galveston, TX 77550-1043, USA.
Delderfield
Susan M
SM
Zhang
Wenru
W
Taglialatela
Giulio
G
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D016922:Cellular Senescence; D006133:Growth Substances / Q000502:physiology*; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis; D016328:NF-kappa B / Q000378:metabolism; D052002:NF-kappa B p50 Subunit; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D006133:Growth Substances; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D014409:Tumor Necrosis Factor-alpha; D007770:L-Lactate Dehydrogenase; D011493:Protein Kinase C