Tumour necrosis factor‐alpha‐ vs. growth factor deprivation‐promoted cell death: different receptor requirements for mediating nerve growth factor‐promoted rescue

Abstract

SummaryPhysiological 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 proinflammatory cytokine tumour necrosis factor alpha (TNF α α α α ) 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 withdrawaland TNF α α α α -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 TNF α α α α -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.

Temperature- and time-dependent changes in TLR2-activated microglial NF-κB activity and concentrations of inflammatory and anti-inflammatory factors

“…Therefore, our findings of temperature-dependent changes in microglial TNF-a production in the early phase and IL-10 and NO production in the late phase may indicate their usefulness as clinical markers for monitoring hypothermia-related neuronal protection and hyperthermia-related neuronal injury. Not only the in vivo findings (of increased CNS levels of pro-and antiinflammatory cytokines and NO after brain injury [16,32,33,36] and the possible importance of their reduction by hypothermia for neuronal protection), but also the in vitro finding (of concentration-dependent TNF-aand NO-induced neuronal cell death [40,41]) support this proposition, although the actual role of these phenomena in this context needs to be further investigated. In addition, when microglial TLR2 was activated, we found that TNF-a production in response to hyperthermia remained increased at the later phase (24 h) compared with normothermia; hence, TNF-a level at the late phase might also be a possible clinical marker for hyperthermia-related neuronal injury.…”

Tumour necrosis factor‐alpha‐ vs. growth factor deprivation‐promoted cell death: distinct converging pathways

“…The transcription factor NF κ B has been shown to be required for PC12 cell survival, both in basal conditions and to promote NGF-mediated rescue from serum-free conditions (Taglialatela et al ., 1997;Pappas et al ., 2003). When activated, homo-or heterodimeric NF κ B translocates to the nucleus where it binds to the DNA and modulates promoter activity of numerous genes including many involved in cell death /survival (Mattson et al , 2000).…”

“…PKC ζ is an important signalling element involved in the maintenance of PC12 cell survival. For example, we have previously shown that in PC12 cells arachidonic acid blocks the activation of PKC ζ , thus leading to decreased activity of NF κ B and ultimately to cell death (Macdonald et al ., 1999;Pappas et al ., 2003).…”

Ras signaling in NGF reduction and TNF-α-related pancreatic β cell apoptosis in hyperglycemic rats

“…Evidence from PC12 cell culture experiments suggested that TNF-a and NGF withdrawal activate a common apoptotic pathway [13]. If considering a lot of similarity between neurons and pancreatic b cells it could be possible that NGF reduction and TNF-a together trigger apoptosis in b cells under hyperglycemic conditions.…”

“…While Trk receptors mediate survival and differentiation [11], the role of p75 NTR is associated with the modulation of apoptosis [12]. Pappas et al [13] demonstrated that in the PC12 cells both TNF-a and growth factor withdrawal induce a common downstream apoptosis pathway including caspase-3 activation. Also, they reported that while TrkA is required for NGFmediated rescue of cell death induced by growth factor withdrawal, the p75 NTR is sufficient for rescuing from TNF-a-promoted cell death.…”