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Silencing survival data
LETTERS
TO THE EDITOR
Silencing survival data In their article, Venters and colleagues1 discuss the important concept that signals that promote neuronal death might do so by suppressing survival signals. They use as a specific example the interaction between tumor necrosis factor-a (TNFa) and insulin-like growth factor 1 (IGF1) in cultured cerebellar granule cells. ‘Silencer of survival signals’ mechanisms are a general concept that have been forwarded by many investigators previously. Indeed, one established example not discussed by Venters et al. involves the same phosphoinositide 3-kinase (PI 3-kinase) – Akt survival pathway activated by IGF1. PTEN is a phosphatase that dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] and focal adhesion kinase. Detachment of cells from their growth substrate is normally a potent stimulus for apoptosis in most cell types, including neurons, and PTEN (phosphatase and tensin homology deleted on chromosome ten) plays an important role in such cell deaths by inhibiting activation of the survival-promoting PI 3-kinase pathway2. A second well-established suppression of survival signals involves ligation of Fas (the receptor for Fas ligand), a potent stimulus for apoptosis in lymphocytes, which acts by inducing cleavage and inactivation of NF-kB, a survival-promoting transcription factor activated by TNFa (Ref. 3). Activation of Fas by the Fas ligand can also result in cleavage of the TNFa receptorassociated protein, TRAF-1, releasing a cleavage product that blocks activation of NF-kB by TNFa (Ref. 4). A final example involves several apoptotic signals, including trophic factor withdrawal, glutamate and oxidative insults, which induce the prostate apoptosis response-4 (Par-4). Par-4 binds to and inhibits the activity of protein kinase Cz, which in turn decreases activation of NF-kB, thus suppressing a survival signal5,6. Many additional examples of the well-established ‘silencer of survival signals’ concept can be found by a Medline search. Therefore, it is perhaps less surprising that Venters et al. found a system in which this concept transpires than is the very claim that TNFa suppresses PI 3-kinase signaling. Numerous reports document activation of PI 3-kinase by TNFa in other cell types7. One possible explanation for the data presented by the authors in their original research report8 is that the 40-min TNFa pretreatment gave sufficient time for TNFa to induce PI 3-kinase, for the kinase activity to subside, and for negative-feedback loops to make the cells refractory to any further stimulation; no tests of acute responses to TNFa were presented. 466
TINS Vol. 23, No. 1, 2000
The manner in which Venter et al. chose to discuss their specific example of inhibition of IGF1 signaling by TNFa in cerebellar neurons is unbalanced. This presentation might have been misleading to readers who are unfamiliar with the literature on TNFa and apoptosis. Examples of indirect evidence suggesting that TNFa can induce apoptosis of neurons were presented, whereas the compelling evidence obtained in many different laboratories that activation of NF-kB by TNFa serves an anti-apoptotic function, was ignored. Studies of tumor cells and lymphocytes have demonstrated unequivocally that TNFa-induced NF-kB activation prevents apoptosis9–11. The fact that TNFa prevents apoptosis is well-established in many different experimental models, including death of cultured hippocampal neurons induced by glutamate12, amyloid bpeptide13 and trophic factor withdrawal14. In addition, NF-kB activation mediates the anti-apoptotic action of NGF in cultured mouse sensory neurons15. Venters and co-workers describe several examples of studies in which manipulations that inhibit TNFa signaling reduce neuronal death. Initially these reports appear to be in direct contradiction with indications that TNFa and activation of NF-kB can promote neuronal survival. However, this conundrum can be reconciled when the neuronal fate is considered in the context of the complex cellular milieu of intact brain. It should be noted that each of the models cited by Venters et al. involves ischemia or HIV infection. In both of these models, activation of glial cells appears to be a crucial requirement for neuronal cell death. TNFa induces activation of microglia and astrocytes, via an NF-kB-mediated mechanism, which can result in production of neurotoxic reactive oxygen species (superoxide and nitric oxide) and excitotoxins16–18. Glial cells were also present in studies of mixed human embryonic cortical cultures in which TNFa was reported to induce neuronal death, in this case excitotoxins released from the glial cells mediated the neurotoxicity of TNFa (Ref. 19). Venters et al. appear to have succeeded in limiting glial growth in their cultures. Nevertheless, their study8 is the first to describe a neuron death-promoting effect of TNFa in cerebellar cell cultures, therefore it is important to further elucidate the underlying mechanism. Indeed, their findings appear to be at odds with another uncited report, in which exposure of cultured cerebellar granule cells to TNFa enhanced survival in either basal conditions20, or in the face
of challenge by amyloid21. Thus, although the ‘silencer of survival signals’ concept might apply to many cases of neuronal death-inducing stimuli, it remains to be established if, and under what circumstances, it applies to the action of TNFa actions on neurons. Mark P. Mattson Laboratory of Neurosciences, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, MD 21224 USA.
Steven W. Barger University of Arkansas for Medical Sciences, Central Arkansas Veterans Health Care System, 4300 W. 7th, Room GB-112, Little Rock, AR 72205 USA. References 1 Venters, D. et al. (2000) A new concept in neurodegeneration: TNFa is a silencer of survival signals. Trends Neurosci. 23, 175–180 2 Tamura, M. et al. (1999) PTEN interactions with focal adhesion kinase and suppression of the extracellular matrixdependent phosphatidylinositol 3kinase/Akt cell survival pathway. J. Biol. Chem. 274, 20693–20703 3 Ravi, R. et al. (1998) CD95 (Fas)-induced caspase-mediated proteolysis of NF-kB. Cancer Res. 58, 882–886 4 Irmler, M. et al. (2000) Caspase-induced inactivation of the anti-apoptotic TRAF1 during Fas ligand-mediated apoptosis. FEBS Lett. 468, 129–133 5 Diaz-Meco, M.T. et al. (1999) Inactivation of the inhibitory kB protein kinase/nuclear factor kB pathway by Par4 expression potentiates tumor necrosis factor a-induced apoptosis. J. Biol. Chem. 274, 19606–19612 6 Camandola, S. and Mattson, M.P. (2000) The pro-apoptotic action of Par-4 involves inhibition of NF-kB activity and suppression of Bcl-2 expression. J. Neurosci. Res. 61, 134–139 7 Reddy, S.A. et al. (2000) Phosphatidylinositol 3-kinase as a mediator of TNFinduced NF-kB activation. J. Immunol. 164, 1355–1363 8 Venters, H.D. et al. (1999) A new mechanism of neurodegeneration: a proinflammatory cytokine inhibits receptor signaling by a survival peptide. Proc. Natl. Acad. Sci. U. S. A. 96, 9879–9884 9 Beg, A.A. and Baltimore, D. (1996). An essential role for NF-kB in preventing TNFa-induced cell death. Science 274, 782–784 10 Van Antwerp, D.J. et al. (1996). Suppression of TNF-a-induced apoptosis by NFkB. Science 274, 787–789 11 Wang, C.Y. et al. (1996) TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kB. Science 274, 784–787 12 Cheng, B. et al. (1994) Tumor necrosis factors protect neurons against excitotoxic/metabolic insults and promote maintenance of calcium homeostasis. Neuron 12, 139–153 13 Barger, S.W. et al. (1995) Tumor necrosis factors a and b protect neurons against amyloid b-peptide toxicity: evidence for involvement of a kB-binding factor and attenuation of peroxide and Ca21 accumulation. Proc. Natl. Acad. Sci. U. S. A. 92, 9328–9332
LETTERS 14 Glazner, G.W. et al. Nuclear factorkappaB mediates the cell survivalpromoting action of activity-dependent neurotrophic factor peptide. J. Neurochem. 75, 101–108 15 Hamanoue, M. et al. (1999) p75-mediated NF-kB activation enhances the survival response of developing sensory neurons to nerve growth factor. Mol. Cell. Neurosci. 14, 28–40 16 Gremo, F. et al. (1997) Features and functions of human microglial cells. Adv. Exp. Med. Biol. 429, 79–97 17 Bauer, M.K. et al. (1997) Expression and regulation of cyclooxygenase-2 in rat microglia. Eur. J. Biochem. 243, 726–731 18 Downen, M. et al. (1999) Neuronal death in cytokine-activated primary human brain cell culture: role of tumor necrosis factor-a. Glia 28, 114–127 19 Gelbard, H.A. et al. (1999) Neurotoxic effects of tumor necrosis factor alpha in primary human neuronal cultures are mediated by activation of the glutamate AMPA receptor subtype: implications for AIDS neuropathogenesis. Dev. Neurosci. 15, 417–422 20 Courtney, M.J. et al. (1997) Neurotrophins protect cultured cerebellar granule neurons against the early phase of cell death by a two-component mechanism. J. Neurosci. 17, 4201–4211 21 Kaltschmidt, B. et al. Inhibition of NF-kB potentiates amyloid b-mediated neuronal apoptosis. Proc. Natl. Acad. Sci. U. S. A. 96, 9409–9414
Reply Mattson and Barger, who are proponents of the tumor necrosis factor a (TNFa)induced neuroprotection theory, missed the point of our review. We clearly stated in our abstract that the silencing of survival signals (SOSS) concept, ‘is applicable to a broad number of receptors’1. We pointed to the well-known ability of TNFa to silence the closely related tyrosine kinase insulin receptor by inhibiting activation of phosphoinositide 3-kinase (PI 3-kinase). It is not the concept of SOSS that is novel but, as our title indicates, its application to TNFainduced neurodegeneration: this is the first time that the lethality of TNFa has been linked to inhibition of a neuronal insulin-like growth factor 1 (IGF1) survival signal. Contrary to claims of Mattson and Barger2, we clearly acknowledged the antiapoptotic role of TNFa by citing three of Mattson’s articles3–5 and by stating, ‘The exact factors responsible for shifting the effect of TNFa from neurotoxicity to neuroprotection are not known...’ (Ref. 1). Mattson and Barger cited data from Courtney et al.6 as proof that TNFa enhances neuronal survival and mistakenly claimed that we ignored this article. However, Courtney et al. themselves described the 20% protective effect of TNFa (10 ng/ml) as ‘modest.’ We did not elaborate on this ‘modest’ neuroprotection because we tried to highlight the forest, not the trees. We do not dispute that
NF-kB provides an anti-apoptotic signal. Importantly, Mattson and Barger failed to mention that, over a concentration range of greater than 5 log doses, TNFa activates NF-kB and mildly protects against amyloid neurotoxicity in cerebellar granule neurons at only one concentration (2 ng/ml but not at 1 or 4 ng/ml)7. This is in stark contrast to the finding that all log concentrations of TNFa between 0.01 and 10.00 ng/ml linearly inhibit IGF1 neuronal survival, even in the relative absence of glia8. Finally, our review cited the emerging evidence that blocking PI 3-kinase activity prior to treatment with TNFa promotes its toxicity9. However, these studies used TNFa at 1000-fold higher concentrations than those needed to inhibit IGF1 survival, and none used primary neurons. We concluded that IGF1 and TNFa receptor antagonism might converge at the level of PI 3-kinase. The survival of cerebellar granule neurons is increased sixfold by IGF1 (Ref. 8). In this system, any neuroprotection afforded by TNFa is no more than background noise. This finding might lead some investigators to conclude that TNFa has no effect on neurons. In fact, activation of the IGF1 survival receptor evinces the potent, normally latent, silencing role of TNFa. It is for this reason that our concept of SOSS highlighted how a proinflammatory cytokine, implicated in a variety of CNS diseases, critically disrupts signaling of a neuronal survival receptor. Keith W. Kelley Homer D. Venters Laboratory of Immunophysiology, Dept of Animal Sciences, University of Illinois, Urbana, IL 61801, USA.
TO THE EDITOR
Robert Dantzer INSERM U394, Integrative Neurobiology, 33077 Bordeaux Cedex, France. References 1 Venters, H.D. et al. (2000) A new concept in neurodegeneration: TNFa is a silencer of survival signals. Trends Neurosci. 23, 175–180 2 Mattson, M.P. and Barger, S.W. (2000) Silencing survival data. Trends Neurosci. 25, 466–467 3 Cheng, B. et al. (1994) Tumor necrosis factors protect neurons against metabolicexcitotoxic insults and promote maintenance of calcium homeostasis. Neuron 12, 139–153 4 Gary, D.S. et al. (1998) Ischemic and excitoxic brain injury is enhanced in mice lacking the small p55 tumor necrosis factor receptor. J. Cereb. Blood Flow Metab. 18, 1283–1287 5 Sullivan, P.G. et al. (1999) Exacerbation of damage and altered NFkB activation in mice lacking tumor necrosis factor receptor after traumatic brain injury. J. Neurosci. 19, 6248–6256 6 Courtney, M.J. et al. (1997) Neurotrophins protect cultured cerebellar granule neurons against the early phase of cell death by a two-component mechanism. J. Neurosci. 17, 4201–4211 7 Kaltschmidt, B. et al. (1999) Inhibition of NF-KB potentiates amyloid b-mediated neuronal apoptosis. Proc. Natl. Acad. Sci. U. S. A. 96, 9409–9414 8 Venters, H.D. et al. (1999) A new mechanism of neurodegeneration: a proinflammatory cytokine inhibits receptor signaling by a survival peptide. Proc. Natl. Acad. Sci. U. S. A. 96, 9879–9884 9 Pastorino, J.G. et al. (1999) Tumor necrosis factor induces phosphorylation and translocation of BAD through a phosphatidylinositide-3-OH kinasedependent pathway. J. Biol. Chem. 274, 19411–19416
Un pour tous, tous pour un Allsopp and Fazakerley present a clear and thought-provoking Viewpoint article1 on the interplay between virus infection and specific nervous-system mechanisms of antiviral defense. Herewith I wish to propose an addition to their hypothesis concerning the potential evolutionary advantage of neuronal apoptosis in the brains of neonates in response to virus infection. The authors postulate that neuronal apoptosis does indeed have an antiviral effect and that viruses would therefore be expected to evolve mechanisms to overcome this. Viruses encode many anti-apoptotic genes, whose actions should maintain the life of infected cells and force infections into long-lasting chronic patterns of progression. This allows viruses to spread from an infected individual for long time periods. Infections indeed occur frequently in the adult brain, where many have a tendency to become chronic, providing the
pathogens (e.g. HIV, measles and HSV-I) with an infectious reservoir that is not easily eliminated by the immune system. The authors propose that neuronal apoptosis is ‘altruistic’ because it rapidly blocks viral spread throughout the infected brain. Because neurons regenerate in neonatal brains, infected animals could still survive into adulthood with a normal complement of neurons. Although the authors propose that neuronal suicide during viral encephalitis represents an evolutionary advantage, they agree that ‘…the proposed argument for altruistic cell suicide as a means of limiting virus infection would not seem to apply in this circumstance (i.e. neonates), as the infection spreads with death of large numbers of cells, tissue destruction and, in many cases, fatal encephalitis in young animals’. This also concurs with the situation in humans, where neonatal CNS infections carry a high mortality. TINS Vol. 23, No. 10, 2000
467
TO THE EDITOR
Silencing survival data In their article, Venters and colleagues1 discuss the important concept that signals that promote neuronal death might do so by suppressing survival signals. They use as a specific example the interaction between tumor necrosis factor-a (TNFa) and insulin-like growth factor 1 (IGF1) in cultured cerebellar granule cells. ‘Silencer of survival signals’ mechanisms are a general concept that have been forwarded by many investigators previously. Indeed, one established example not discussed by Venters et al. involves the same phosphoinositide 3-kinase (PI 3-kinase) – Akt survival pathway activated by IGF1. PTEN is a phosphatase that dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] and focal adhesion kinase. Detachment of cells from their growth substrate is normally a potent stimulus for apoptosis in most cell types, including neurons, and PTEN (phosphatase and tensin homology deleted on chromosome ten) plays an important role in such cell deaths by inhibiting activation of the survival-promoting PI 3-kinase pathway2. A second well-established suppression of survival signals involves ligation of Fas (the receptor for Fas ligand), a potent stimulus for apoptosis in lymphocytes, which acts by inducing cleavage and inactivation of NF-kB, a survival-promoting transcription factor activated by TNFa (Ref. 3). Activation of Fas by the Fas ligand can also result in cleavage of the TNFa receptorassociated protein, TRAF-1, releasing a cleavage product that blocks activation of NF-kB by TNFa (Ref. 4). A final example involves several apoptotic signals, including trophic factor withdrawal, glutamate and oxidative insults, which induce the prostate apoptosis response-4 (Par-4). Par-4 binds to and inhibits the activity of protein kinase Cz, which in turn decreases activation of NF-kB, thus suppressing a survival signal5,6. Many additional examples of the well-established ‘silencer of survival signals’ concept can be found by a Medline search. Therefore, it is perhaps less surprising that Venters et al. found a system in which this concept transpires than is the very claim that TNFa suppresses PI 3-kinase signaling. Numerous reports document activation of PI 3-kinase by TNFa in other cell types7. One possible explanation for the data presented by the authors in their original research report8 is that the 40-min TNFa pretreatment gave sufficient time for TNFa to induce PI 3-kinase, for the kinase activity to subside, and for negative-feedback loops to make the cells refractory to any further stimulation; no tests of acute responses to TNFa were presented. 466
TINS Vol. 23, No. 1, 2000
The manner in which Venter et al. chose to discuss their specific example of inhibition of IGF1 signaling by TNFa in cerebellar neurons is unbalanced. This presentation might have been misleading to readers who are unfamiliar with the literature on TNFa and apoptosis. Examples of indirect evidence suggesting that TNFa can induce apoptosis of neurons were presented, whereas the compelling evidence obtained in many different laboratories that activation of NF-kB by TNFa serves an anti-apoptotic function, was ignored. Studies of tumor cells and lymphocytes have demonstrated unequivocally that TNFa-induced NF-kB activation prevents apoptosis9–11. The fact that TNFa prevents apoptosis is well-established in many different experimental models, including death of cultured hippocampal neurons induced by glutamate12, amyloid bpeptide13 and trophic factor withdrawal14. In addition, NF-kB activation mediates the anti-apoptotic action of NGF in cultured mouse sensory neurons15. Venters and co-workers describe several examples of studies in which manipulations that inhibit TNFa signaling reduce neuronal death. Initially these reports appear to be in direct contradiction with indications that TNFa and activation of NF-kB can promote neuronal survival. However, this conundrum can be reconciled when the neuronal fate is considered in the context of the complex cellular milieu of intact brain. It should be noted that each of the models cited by Venters et al. involves ischemia or HIV infection. In both of these models, activation of glial cells appears to be a crucial requirement for neuronal cell death. TNFa induces activation of microglia and astrocytes, via an NF-kB-mediated mechanism, which can result in production of neurotoxic reactive oxygen species (superoxide and nitric oxide) and excitotoxins16–18. Glial cells were also present in studies of mixed human embryonic cortical cultures in which TNFa was reported to induce neuronal death, in this case excitotoxins released from the glial cells mediated the neurotoxicity of TNFa (Ref. 19). Venters et al. appear to have succeeded in limiting glial growth in their cultures. Nevertheless, their study8 is the first to describe a neuron death-promoting effect of TNFa in cerebellar cell cultures, therefore it is important to further elucidate the underlying mechanism. Indeed, their findings appear to be at odds with another uncited report, in which exposure of cultured cerebellar granule cells to TNFa enhanced survival in either basal conditions20, or in the face
of challenge by amyloid21. Thus, although the ‘silencer of survival signals’ concept might apply to many cases of neuronal death-inducing stimuli, it remains to be established if, and under what circumstances, it applies to the action of TNFa actions on neurons. Mark P. Mattson Laboratory of Neurosciences, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, MD 21224 USA.
Steven W. Barger University of Arkansas for Medical Sciences, Central Arkansas Veterans Health Care System, 4300 W. 7th, Room GB-112, Little Rock, AR 72205 USA. References 1 Venters, D. et al. (2000) A new concept in neurodegeneration: TNFa is a silencer of survival signals. Trends Neurosci. 23, 175–180 2 Tamura, M. et al. (1999) PTEN interactions with focal adhesion kinase and suppression of the extracellular matrixdependent phosphatidylinositol 3kinase/Akt cell survival pathway. J. Biol. Chem. 274, 20693–20703 3 Ravi, R. et al. (1998) CD95 (Fas)-induced caspase-mediated proteolysis of NF-kB. Cancer Res. 58, 882–886 4 Irmler, M. et al. (2000) Caspase-induced inactivation of the anti-apoptotic TRAF1 during Fas ligand-mediated apoptosis. FEBS Lett. 468, 129–133 5 Diaz-Meco, M.T. et al. (1999) Inactivation of the inhibitory kB protein kinase/nuclear factor kB pathway by Par4 expression potentiates tumor necrosis factor a-induced apoptosis. J. Biol. Chem. 274, 19606–19612 6 Camandola, S. and Mattson, M.P. (2000) The pro-apoptotic action of Par-4 involves inhibition of NF-kB activity and suppression of Bcl-2 expression. J. Neurosci. Res. 61, 134–139 7 Reddy, S.A. et al. (2000) Phosphatidylinositol 3-kinase as a mediator of TNFinduced NF-kB activation. J. Immunol. 164, 1355–1363 8 Venters, H.D. et al. (1999) A new mechanism of neurodegeneration: a proinflammatory cytokine inhibits receptor signaling by a survival peptide. Proc. Natl. Acad. Sci. U. S. A. 96, 9879–9884 9 Beg, A.A. and Baltimore, D. (1996). An essential role for NF-kB in preventing TNFa-induced cell death. Science 274, 782–784 10 Van Antwerp, D.J. et al. (1996). Suppression of TNF-a-induced apoptosis by NFkB. Science 274, 787–789 11 Wang, C.Y. et al. (1996) TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kB. Science 274, 784–787 12 Cheng, B. et al. (1994) Tumor necrosis factors protect neurons against excitotoxic/metabolic insults and promote maintenance of calcium homeostasis. Neuron 12, 139–153 13 Barger, S.W. et al. (1995) Tumor necrosis factors a and b protect neurons against amyloid b-peptide toxicity: evidence for involvement of a kB-binding factor and attenuation of peroxide and Ca21 accumulation. Proc. Natl. Acad. Sci. U. S. A. 92, 9328–9332
LETTERS 14 Glazner, G.W. et al. Nuclear factorkappaB mediates the cell survivalpromoting action of activity-dependent neurotrophic factor peptide. J. Neurochem. 75, 101–108 15 Hamanoue, M. et al. (1999) p75-mediated NF-kB activation enhances the survival response of developing sensory neurons to nerve growth factor. Mol. Cell. Neurosci. 14, 28–40 16 Gremo, F. et al. (1997) Features and functions of human microglial cells. Adv. Exp. Med. Biol. 429, 79–97 17 Bauer, M.K. et al. (1997) Expression and regulation of cyclooxygenase-2 in rat microglia. Eur. J. Biochem. 243, 726–731 18 Downen, M. et al. (1999) Neuronal death in cytokine-activated primary human brain cell culture: role of tumor necrosis factor-a. Glia 28, 114–127 19 Gelbard, H.A. et al. (1999) Neurotoxic effects of tumor necrosis factor alpha in primary human neuronal cultures are mediated by activation of the glutamate AMPA receptor subtype: implications for AIDS neuropathogenesis. Dev. Neurosci. 15, 417–422 20 Courtney, M.J. et al. (1997) Neurotrophins protect cultured cerebellar granule neurons against the early phase of cell death by a two-component mechanism. J. Neurosci. 17, 4201–4211 21 Kaltschmidt, B. et al. Inhibition of NF-kB potentiates amyloid b-mediated neuronal apoptosis. Proc. Natl. Acad. Sci. U. S. A. 96, 9409–9414
Reply Mattson and Barger, who are proponents of the tumor necrosis factor a (TNFa)induced neuroprotection theory, missed the point of our review. We clearly stated in our abstract that the silencing of survival signals (SOSS) concept, ‘is applicable to a broad number of receptors’1. We pointed to the well-known ability of TNFa to silence the closely related tyrosine kinase insulin receptor by inhibiting activation of phosphoinositide 3-kinase (PI 3-kinase). It is not the concept of SOSS that is novel but, as our title indicates, its application to TNFainduced neurodegeneration: this is the first time that the lethality of TNFa has been linked to inhibition of a neuronal insulin-like growth factor 1 (IGF1) survival signal. Contrary to claims of Mattson and Barger2, we clearly acknowledged the antiapoptotic role of TNFa by citing three of Mattson’s articles3–5 and by stating, ‘The exact factors responsible for shifting the effect of TNFa from neurotoxicity to neuroprotection are not known...’ (Ref. 1). Mattson and Barger cited data from Courtney et al.6 as proof that TNFa enhances neuronal survival and mistakenly claimed that we ignored this article. However, Courtney et al. themselves described the 20% protective effect of TNFa (10 ng/ml) as ‘modest.’ We did not elaborate on this ‘modest’ neuroprotection because we tried to highlight the forest, not the trees. We do not dispute that
NF-kB provides an anti-apoptotic signal. Importantly, Mattson and Barger failed to mention that, over a concentration range of greater than 5 log doses, TNFa activates NF-kB and mildly protects against amyloid neurotoxicity in cerebellar granule neurons at only one concentration (2 ng/ml but not at 1 or 4 ng/ml)7. This is in stark contrast to the finding that all log concentrations of TNFa between 0.01 and 10.00 ng/ml linearly inhibit IGF1 neuronal survival, even in the relative absence of glia8. Finally, our review cited the emerging evidence that blocking PI 3-kinase activity prior to treatment with TNFa promotes its toxicity9. However, these studies used TNFa at 1000-fold higher concentrations than those needed to inhibit IGF1 survival, and none used primary neurons. We concluded that IGF1 and TNFa receptor antagonism might converge at the level of PI 3-kinase. The survival of cerebellar granule neurons is increased sixfold by IGF1 (Ref. 8). In this system, any neuroprotection afforded by TNFa is no more than background noise. This finding might lead some investigators to conclude that TNFa has no effect on neurons. In fact, activation of the IGF1 survival receptor evinces the potent, normally latent, silencing role of TNFa. It is for this reason that our concept of SOSS highlighted how a proinflammatory cytokine, implicated in a variety of CNS diseases, critically disrupts signaling of a neuronal survival receptor. Keith W. Kelley Homer D. Venters Laboratory of Immunophysiology, Dept of Animal Sciences, University of Illinois, Urbana, IL 61801, USA.
TO THE EDITOR
Robert Dantzer INSERM U394, Integrative Neurobiology, 33077 Bordeaux Cedex, France. References 1 Venters, H.D. et al. (2000) A new concept in neurodegeneration: TNFa is a silencer of survival signals. Trends Neurosci. 23, 175–180 2 Mattson, M.P. and Barger, S.W. (2000) Silencing survival data. Trends Neurosci. 25, 466–467 3 Cheng, B. et al. (1994) Tumor necrosis factors protect neurons against metabolicexcitotoxic insults and promote maintenance of calcium homeostasis. Neuron 12, 139–153 4 Gary, D.S. et al. (1998) Ischemic and excitoxic brain injury is enhanced in mice lacking the small p55 tumor necrosis factor receptor. J. Cereb. Blood Flow Metab. 18, 1283–1287 5 Sullivan, P.G. et al. (1999) Exacerbation of damage and altered NFkB activation in mice lacking tumor necrosis factor receptor after traumatic brain injury. J. Neurosci. 19, 6248–6256 6 Courtney, M.J. et al. (1997) Neurotrophins protect cultured cerebellar granule neurons against the early phase of cell death by a two-component mechanism. J. Neurosci. 17, 4201–4211 7 Kaltschmidt, B. et al. (1999) Inhibition of NF-KB potentiates amyloid b-mediated neuronal apoptosis. Proc. Natl. Acad. Sci. U. S. A. 96, 9409–9414 8 Venters, H.D. et al. (1999) A new mechanism of neurodegeneration: a proinflammatory cytokine inhibits receptor signaling by a survival peptide. Proc. Natl. Acad. Sci. U. S. A. 96, 9879–9884 9 Pastorino, J.G. et al. (1999) Tumor necrosis factor induces phosphorylation and translocation of BAD through a phosphatidylinositide-3-OH kinasedependent pathway. J. Biol. Chem. 274, 19411–19416
Un pour tous, tous pour un Allsopp and Fazakerley present a clear and thought-provoking Viewpoint article1 on the interplay between virus infection and specific nervous-system mechanisms of antiviral defense. Herewith I wish to propose an addition to their hypothesis concerning the potential evolutionary advantage of neuronal apoptosis in the brains of neonates in response to virus infection. The authors postulate that neuronal apoptosis does indeed have an antiviral effect and that viruses would therefore be expected to evolve mechanisms to overcome this. Viruses encode many anti-apoptotic genes, whose actions should maintain the life of infected cells and force infections into long-lasting chronic patterns of progression. This allows viruses to spread from an infected individual for long time periods. Infections indeed occur frequently in the adult brain, where many have a tendency to become chronic, providing the
pathogens (e.g. HIV, measles and HSV-I) with an infectious reservoir that is not easily eliminated by the immune system. The authors propose that neuronal apoptosis is ‘altruistic’ because it rapidly blocks viral spread throughout the infected brain. Because neurons regenerate in neonatal brains, infected animals could still survive into adulthood with a normal complement of neurons. Although the authors propose that neuronal suicide during viral encephalitis represents an evolutionary advantage, they agree that ‘…the proposed argument for altruistic cell suicide as a means of limiting virus infection would not seem to apply in this circumstance (i.e. neonates), as the infection spreads with death of large numbers of cells, tissue destruction and, in many cases, fatal encephalitis in young animals’. This also concurs with the situation in humans, where neonatal CNS infections carry a high mortality. TINS Vol. 23, No. 10, 2000
467