Tumor Necrosis Factor (TNF)-mediated Neuroprotection against Glutamate-induced Excitotoxicity Is Enhanced by N-Methyl-D-aspartate Receptor Activation

We have previously shown that two tumor necrosis factor (TNF) receptors (TNFR) exhibit antagonistic functions during neurodegenerative processes in vivo with TNFR1 aggravating and TNFR2 reducing neuronal cell loss, respectively. To elucidate the neuroprotective signaling pathways of TNFR2, we investigated glutamate-induced excitotoxicity in primary cortical neurons. TNF-expressing neurons from TNF-transgenic mice were found to be strongly protected from glutamate-induced apoptosis. Neurons from wild type and TNFR1-/- mice prestimulated with TNF or agonistic TNFR2-specific antibodies were also resistant to excitotoxicity, whereas TNFR2-/- neurons died upon glutamate and/or TNF exposures. Both protein kinase B/Akt and nuclear factor-κB (NF-κB) activation were apparent upon TNF treatment. Both TNFR1 and TNFR2 induced the NF-κB pathway, yet with distinguishable kinetics and upstream activating components, TNFR1 only induced transient NF-κB activation, whereas TNFR2 facilitated long term phosphatidylinositol 3-kinase-dependent NF-κB activation strictly. Glutamate-induced triggering of the ionotropic N-methyl-d-aspartate receptor was required for the enhanced and persistent phosphatidylinositol 3-kinase-dependent NF-κB activation by TNFR2, indicating a positive cooperation of TNF and neurotransmitter-induced signal pathways. TNFR2-induced persistent NF-κB activity was essential for neuronal survival. Thus, the duration of NF-κB activation is a critical determinant for sensitivity toward excitotoxic stress and is dependent on a differential upstream signal pathway usage of the two TNFRs. We have previously shown that two tumor necrosis factor (TNF) receptors (TNFR) exhibit antagonistic functions during neurodegenerative processes in vivo with TNFR1 aggravating and TNFR2 reducing neuronal cell loss, respectively. To elucidate the neuroprotective signaling pathways of TNFR2, we investigated glutamate-induced excitotoxicity in primary cortical neurons. TNF-expressing neurons from TNF-transgenic mice were found to be strongly protected from glutamate-induced apoptosis. Neurons from wild type and TNFR1-/- mice prestimulated with TNF or agonistic TNFR2-specific antibodies were also resistant to excitotoxicity, whereas TNFR2-/- neurons died upon glutamate and/or TNF exposures. Both protein kinase B/Akt and nuclear factor-κB (NF-κB) activation were apparent upon TNF treatment. Both TNFR1 and TNFR2 induced the NF-κB pathway, yet with distinguishable kinetics and upstream activating components, TNFR1 only induced transient NF-κB activation, whereas TNFR2 facilitated long term phosphatidylinositol 3-kinase-dependent NF-κB activation strictly. Glutamate-induced triggering of the ionotropic N-methyl-d-aspartate receptor was required for the enhanced and persistent phosphatidylinositol 3-kinase-dependent NF-κB activation by TNFR2, indicating a positive cooperation of TNF and neurotransmitter-induced signal pathways. TNFR2-induced persistent NF-κB activity was essential for neuronal survival. Thus, the duration of NF-κB activation is a critical determinant for sensitivity toward excitotoxic stress and is dependent on a differential upstream signal pathway usage of the two TNFRs. Tumor necrosis factor (TNF) 1The abbreviations used are: TNF, tumor necrosis factor; TNFR, TNF receptor; PI3K, phosphatidylinositol 3-kinase; PKB, protein kinase B; UTR, untranslated region; NF-κB, nuclear factor-κB; NMDA, N-methyl-d-aspartate; NMDAR, NMDA receptor; NR2B, NMDAR subunit 2B; Z, benzyloxycarbonyl; fmk, fluoromethyl ketone; PBS, phosphate-buffered saline; DTT, dithiothreitol; EMSA, electrophoretic mobility shift assay; IKK, IκB kinase; ANOVA, analysis of variance. is a prominent proinflammatory mediator that has been causally associated with the pathophysiology of several acute and chronic diseases, in particular rheumatoid arthritis and Morbus Crohn (1Fleischmann R. Iqbal I. Nandeshwar P. Quiceno A. Expert Opin. Drug Saf. 2002; 25: 173-197Google Scholar, 2Mueller C. Immunology. 2002; 105: 1-8Google Scholar). Up-regulated TNF expression has also been found in various neurodegenerative diseases such as cerebral malaria, AIDS dementia, Alzheimer's disease, multiple sclerosis, and stroke, suggesting a potential pathogenic role of TNF in these diseases as well (3Lou J. Lucas R. Grau G.E. Clin. Microbiol. Rev. 2001; 14: 810-820Google Scholar, 4Tyor W.R. Wesselingh S.L. Griffin J.W. McArthur J.C. Griffin D.E. J. Acquired Immune Defic. Syndr. Hum. Retrovirol. 1995; 9: 379-388Google Scholar, 5Perry R.T. Collins J.S. Wiener H. Acton R. Go R.C. Neurobiol. Aging. 2001; 22: 873-883Google Scholar, 6Probert L. Akassoglou K. Glia. 2001; 36: 212-219Google Scholar, 7Clark W.M. Lutsep H.L. Expert Opin. Biol. Ther. 2001; 1: 227-237Google Scholar). The membrane-expressed form of TNF signals through both TNF receptors (TNFR1 and TNFR2), whereas soluble TNF proteolytically cleaved from the membrane form acts mainly via TNFR1 (8Grell M. Douni E. Wajant H. Lohden M. Clauss M. Maxeiner B. Georgopoulos S. Lesslauer W. Kollias G. Pfizenmaier K. Scheurich P. Cell. 1995; 83: 793-802Google Scholar). Signal pathways initiated from the death domain-containing TNFR1, leading to both proapoptotic and anti-apoptotic cellular responses, have been studied in great detail (9Wajant H. Pfizenmaier K. Scheurich P. Cell Death Differ. 2003; 10: 45-65Google Scholar). In contrast, there is less information regarding the molecular mechanisms surrounding signal pathways and cellular responses solely initiated via TNFR2 because of concomitant TNFR1 signals in normal situations. The evaluation of the physiological role of TNFR2 by large depends on data obtained from TNFR1-/- mice. We have recently investigated the role of TNF and its receptors in retinal ischemia and unraveled an antagonistic function of TNFR1 and TNFR2. TNFR2 exerts neuroprotection in a phosphatidylinositol 3-kinase (PI3K) dependent manner, which is counterbalanced by the neurodegenerative action of TNFR1 (10Fontaine V. Mohand-Said S. Hanoteau N. Fuchs C. Pfizenmaier K. Eisel U. J. Neurosci. 2002; 22: 1-7Google Scholar). TNFR1 has also been associated with the cell death of hippocampal neurons responding to TNF (11Yang L. Lindholm K. Konishi Y. Li R. Shen Y. J. Neurosci. 2002; 22: 3025-3032Google Scholar), whereas inhibition of TNFR2 expression by the use of antisense oligonucleotides sensitized neuronal-like cells toward apoptosis (12Shen Y. Li R. Shiosaki K. J. Biol. Chem. 1997; 272: 3550-3553Google Scholar). To elucidate the neuroprotective signal pathways emanating from TNFR2, we have established an in vitro model of apoptosis induction of primary cortical neurons by glutamate-triggered excitotoxicity to study mechanisms controlling apoptosis sensitivity of neurons within wild type (C57BL/6) and TNF transgenic TNFR1-/- and TNFR2-/- mice. Our data reveal, for the first time, differential activation kinetics of NF-κB and differential usage of upstream signaling components by TNFR1 and TNFR2. TNFR2, but not TNFR1, induces persistent NF-κB activation via a signaling pathway involving PI3K and PKB/Akt, which is strongly enhanced by N-methyl-d-aspartate receptor co-stimulation. Generation of Transgenic Mice with Brain-specific TNF Expression—Transgenic mice were developed by pronuclear injection in general as previously described (13Eisel U. Reynolds K. Riddick M. Zimmer A. Niemann H. Zimmer A. EMBO J. 1993; 12: 3365-3372Google Scholar). A construct consisting of the murine NMDAR subunit 2B (NR2B) promoter and the first three of the of the was with the of the first of the murine TNF with the of of the TNF by the of the J. L. H. Georgopoulos S. E. Kollias G. EMBO J. 10: Scholar). were investigated and TNF expression only in the of and duration of The expression was by in as described previously M. I. Pfizenmaier K. Eisel U. Scholar). The a of the murine TNF was with or for of a or antisense or Cell were as were the were and the were Neurons were by were a of or or on with and with a of and was used as the in cells were with for to cell the was and was were with of glutamate for A and and or for with the of TNF and A and or agonistic antibodies by a of glutamate and the of the cell cells were to the glutamate with an of PI3K or NMDAR or NF-κB or To the kinetics of cell death primary cortical neurons were for with and glutamate and cell was the or and antibodies were by a to triggering of the anti-apoptotic signals via in sensitivity for glutamate-induced excitotoxicity of primary cortical neurons from in the or of the NMDAR and wild type and and TNFR1-/- and TNFR2-/- TNF of primary neuronal to excitotoxic of glutamate in the or of the and and and and glutamate to of the for of the cell shown as an for wild type the PI3K neuroprotection in transgenic neurons and and with Cell death in and was by as described activation is for glutamate neuroprotection in the or of the and wild type and TNFR1-/- and TNFR2-/- and glutamate to of the for of the cell shown as an for wild type glutamate induced cell death in the or of the and and and and glutamate to of the for of the cell shown as an for wild type neuroprotection in the or of the IκB and and and and glutamate to of the for of the cell shown as an for wild type glutamate of transgenic neurons be by both and Cell death in and was by as described antibodies TNF in primary cortical wild type of primary neuronal by agonistic to excitotoxic of glutamate in the or of and wild type and glutamate to of the and neuroprotection of primary neuronal by agonistic to excitotoxic of glutamate in the or of or and and glutamate to of the Cell death in and was by as described of Cell was by the as described previously J. Scholar). cortical neurons were in a of and as of an was to a cells were by of of for The of well was with an with a from primary cortical neurons were by with phosphate-buffered by the of of the cell DTT, and were on for of was for and were by The were for in and of protein was by to a membrane were with a primary and a enhanced to the antibodies were a for the Cell Cell IκB Cell TNF and glutamate receptor and were with in PBS, for with for and with in with a or was by a with a or Neurons were with a for and a or cells were a protein and a The cell in of apoptosis induction was of and cells by with an for by a with for nuclear were with for and with for were with antibodies and in with a or in and with to the of nuclear primary cortical neurons were with PBS, in of DTT, and on for of was for and were by and in DTT, and for and The nuclear was used for The NF-κB was with was by of nuclear protein with of in a DTT, and The was for was by with NF-κB were on and by nuclear were with or antibodies for Generation and of Transgenic transgenic the role of TNF in the were to a and of TNF which was associated with various L. Akassoglou K. M. G. Kollias G. U. S. A. 1995; Scholar, K. L. G. Kollias G. J. 1997; Scholar, K. J. G. M. H. Kollias G. L. J. Scholar, G. J. Akassoglou K. H. Kollias G. L. J. Scholar). To TNF we have the promoter of the murine NMDA receptor subunit to mice with a and neuronal TNF The expression of subunit is to and mainly in cortical and hippocampal of the M. Y. K. M. J. 1993; Scholar, H. N. B. 12: Scholar). To expression of TNF in transgenic the of the which was shown to the expression was also in the construct G. J. Akassoglou K. H. Kollias G. L. J. Scholar, M. A. J. Biol. Chem. Scholar). TNF expression was by in in and of primary neuronal cells and and in the responses such as or were as from with and of TNF expression L. Akassoglou K. M. G. Kollias G. U. S. A. 1995; Scholar, K. L. G. Kollias G. J. 1997; Scholar, K. J. G. M. H. Kollias G. L. J. Scholar, G. J. Akassoglou K. H. Kollias G. L. J. Scholar). in of TNF expression and cells positive for or as activation be and The data that TNF expression is in with the of the H. N. B. 12: Scholar, M. A. J. Biol. Chem. Scholar). of TNF protein and activation in of transgenic but not of in vivo expression of the In TNF be on the cell membrane and and in the of transgenic neurons cells of soluble TNF in but not in that of neurons from as by a not S.L. Scholar, S. A. J. Scholar). on the promoter activity as by of in wild type neurons not Neurons from Glutamate-induced Cell of wild type murine primary cortical neurons to of glutamate to a and induction of cell death A and which was by the nuclear and inhibition of neuronal cell death by an of the NMDA is of excitotoxic induction of which is in with Scholar). cortical neurons from transgenic in to wild type and and were found to be resistant to glutamate-triggered excitotoxicity To the of TNF expression of TNF transgenic wild type and neuronal cells were for with these toward glutamate-induced apoptosis be induced in wild type to an in TNFR1-/- neuronal cells contrast, TNFR2-/- neurons were not only to glutamate-induced cell death but also died upon TNF TNF of neuronal or to glutamate was found to be not data that the of primary cortical neurons toward an excitotoxic a TNF signal via TNFR2. ischemia of the of TNFR1-/- we have recently shown that the PI3K neuronal (10Fontaine V. Mohand-Said S. Hanoteau N. Fuchs C. Pfizenmaier K. Eisel U. J. Neurosci. 2002; 22: 1-7Google Scholar). we have investigated the role of PI3K in the glutamate-induced in vitro excitotoxicity The glutamate of transgenic cortical neurons and neurons of wild type or TNFR1-/- mice was by we found that of wild type and TNFR1-/- neurons required in vitro with TNF, the of the PI3K as as the excitotoxic the of neurons that in to a TNF the activation of a PI3K pathway has to within a the excitotoxic for proapoptotic and anti-apoptotic pathways emanating from TNFR1 and TNFR2, was obtained by the use of agonistic antibodies C. M. W. J. Scholar), of receptor in wild type neurons. of the antibodies was by on TNFR1-/- and TNFR2-/- neurons not The neuronal cell death in wild type neurons in a and not from glutamate-induced apoptosis of TNFR2 but to an inhibition of excitotoxicity the of PI3K by the whereas the cell death was not by the PI3K The critical of PI3K signaling was by usage of TNFR2 or TNF not NMDAR TNFR2-induced is to be a prominent and protein of PI3K 2002; Scholar). of the and of cortical neurons from glutamate-induced we investigated activity during excitotoxic of and wild and TNFR2-/- mice as well as that of transgenic mice. were with protein from cortical neurons with TNF and/or glutamate in the or of a NMDAR or a PI3K and persistent was in both TNFR1-/- and wild type neurons TNF and glutamate and was by in wild type cells and in TNFR1-/- cells and In TNFR2-/- only a transient activation was upon glutamate and TNF and data that the persistent is and we to an of signal pathway by the In to wild and TNFR2-/- of were in transgenic neurons in vitro TNF which is in with TNF expression in these neurons. from the was of the and NMDAR TNFR2-induced NF-κB activation in primary cortical neurons was by of nuclear as well as by the and The TNF of TNFR1-/- or TNFR2-/- neurons in NF-κB activation NF-κB of TNFR1 a and whereas NF-κB of and was type which both kinetics glutamate of a of the NF-κB activity be by nuclear and in wild type and in TNFR1-/- whereas TNFR2-/- neurons of NF-κB activation by glutamate and and upon glutamate NF-κB activation was and and In wild type NF-κB activity and strongly glutamate and for and and In these the was strongly by and during the first and and and NF-κB activity was by in glutamate an of a pathway for NF-κB activation in wild type in particular of glutamate TNFR1-/- neurons activation kinetics to wild type neurons with NF-κB activation was by and and suggesting in cortical neuronal NF-κB activation is the of the of the NF-κB by the essential role of NMDAR in wild type and TNFR1-/- neurons and contrast, PI3K of neuronal NF-κB activation was less the NF-κB of TNFR2-/- neurons was by and and that NF-κB activation not and through NMDAR to transgenic neurons NF-κB activity because of the expression of TNF and glutamate enhanced nuclear NF-κB and its activation and which be by and and and by and glutamate and and of transgenic neurons with NF-κB activation as well indicating that chronic TNF expression in these cells a on TNF signaling toward TNFR2 pathways. analysis antibodies and and as the NF-κB in of the the is in with the that both TNFR1 and TNFR2 use the NF-κB pathway (9Wajant H. Pfizenmaier K. Scheurich P. Cell Death Differ. 2003; 10: 45-65Google Scholar), the differential kinetics of activation and sensitivity toward PI3K in primary cortical neurons upstream signal pathway usage of the two TNFRs. induction of NF-κB is whereas TNFR2 a NF-κB The is and enhanced by of the ionotropic NMDA In contrast, the NF-κB activation is less dependent on PI3K and not enhanced by NMDA receptor in primary cortical of and in primary cortical wild type neurons. a with and the a with kinetics of nuclear of wild kinetics of TNF or and glutamate as wild kinetics of in transgenic neurons or and glutamate as in and was by within a of the of neuronal cells with NF-κB nuclear shown in A with TNF and of the the of three and the of the data was by NF-κB activation in primary cortical neurons. and for NF-κB activity in primary cortical of nuclear of and TNFR2-/- neurons TNF, or and glutamate as were with a NF-κB and as described nuclear from transgenic neurons or and glutamate as were with a NF-κB and as described for of and transgenic neurons were with or antibodies and as described of IκB to PI3K the molecular of NF-κB activation, and were in transgenic or wild and TNFR2-/- neurons. In TNFR1-/- the and of IκB and was as with wild type cells sensitivity of IκB and was in TNFR1-/- neurons as with wild type neurons with the NF-κB activation kinetics in TNFR2-/- only transient IκB and were in these cells that were transgenic neurons and to the expression of is with the activation of NF-κB in these cells and IκB and the of IκB in transgenic neurons indicating signaling through TNFR2. The transient in IκB concomitant TNFR1 activity and/or To IκB were in the of the which the in IκB protein in of the neuronal and NF-κB a of the role of NF-κB from the excitotoxic of cortical we NF-κB by the use of three to with NF-κB activation the of the via the of with and the with of via J. A. A. Y. Y. L. J. Biol. Chem. Scholar, C. C. Y. L. Scholar, J.W. R. G. J. Collins J. Biol. Chem. 1997; 272: Scholar, V. J. N. 2001; Scholar). and a in the in vitro neuronal of these in TNFR1-/- and wild type cortical neurons TNFR2-/- neurons as a and of the on the excitotoxic sensitivity of these cells the of toward glutamate-induced cell death be by with NF-κB activation data that NF-κB activation and of anti-apoptotic a role in of neurons from excitotoxic We have recently shown the critical of TNF and its receptors in retinal ischemia in which were protected from whereas developed and enhanced neuronal with wild type data a potential antagonistic function of with to neuronal upon stress signals and/or (10Fontaine V. Mohand-Said S. Hanoteau N. Fuchs C. Pfizenmaier K. Eisel U. J. Neurosci. 2002; 22: 1-7Google Scholar). we that the to cortical neurons and for the of the signal pathway an in vitro model of glutamate-induced cell death of primary cortical neurons. in vivo (10Fontaine V. Mohand-Said S. Hanoteau N. Fuchs C. Pfizenmaier K. Eisel U. J. Neurosci. 2002; 22: 1-7Google and the in vitro for a anti-apoptotic pathway via TNFR2. a transgenic TNF the of the murine NMDAR subunit promoter in TNF activity apparent or M. K. K. and U. L. M. neurons from these mice were protected from glutamate-induced apoptosis. we have used the TNF of wild type and primary cortical neurons to the with neurons from TNF transgenic mice and that neurons from wild type and TNFR1-/- mice were whereas primary neurons from TNFR2-/- mice were to cell we by of NF-κB activation and by inhibition of signal pathway components in the that neuroprotection is via a pathway in which the duration of NF-κB activation is the critical determinant in toward excitotoxic The of soluble murine TNF required to in vitro is of an and critical role of TNFR2, which has a for soluble TNF and a signal as with TNFR1, TNF for signaling M. Wajant H. G. Scheurich P. U. S. A. Scholar). the primary neurons from the TNF transgenic that protected from excitotoxicity TNF not only in its form but also the neuronal cell a for TNFR2 Both an and a signaling of membrane-expressed TNF cortical neurons both we membrane TNF expression in the transgenic the neuroprotective TNFR2 pathway is TNFR1 for differential of the two in signaling neuronal from the use of agonistic antibodies but not from A differential role of TNFR1 and TNFR2 has also been for hippocampal neurons responding to TNF with TNFR1 both NF-κB activation and cell whereas TNFR2 was found to protein kinase (11Yang L. Lindholm K. Konishi Y. Li R. Shen Y. J. Neurosci. 2002; 22: 3025-3032Google Scholar). study the of activation the of apoptosis in these cells in the of an NF-κB activation (11Yang L. Lindholm K. Konishi Y. Li R. Shen Y. J. Neurosci. 2002; 22: 3025-3032Google Scholar), which is to an role in neuroprotection J. Biol. 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Cell 2002; 14: Scholar, J. Biol. Chem. 2001; Scholar, Scholar, Scholar, H. P. S. Cell. 1995; Scholar). with established cell that as an kinase in to TNF Scholar). data that is the of in the in activation and H. R. Li J. Biol. Chem. Scholar). Our data with primary neurons activation in a TNFR2-specific PI3K of IκB and activation of as well as neuroprotection is in with a cell function of in the NF-κB NF-κB activation via pathways not cortical neurons from glutamate-induced which is in with data from hippocampal neurons responding to TNF only (11Yang L. Lindholm K. Konishi Y. Li R. Shen Y. J. 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The of a cell with the of of these signaling not only the potential to receptor signals but also the kinetics and duration of NF-κB Our data a that in the signal (TNFR1 TNFR2 activating the a signal death by of a differential duration of the of critical the NMDA receptor with to a of and NF-κB activation, an as of yet a TNFR2, and the ionotropic NMDA be that positive cooperation with to and NF-κB activation as a to signals emanating from In of only persistent NF-κB activation is associated with from cell Our data that a action of TNFR2 with the ionotropic NMDA which or the of The molecular mechanisms of the cooperation not yet is apparent from not that the signals emanating from TNFR2 have to the excitotoxic first be in with of an of the cell via an a of NMDAR inhibition of the PI3K pathway glutamate not only the and of and NF-κB but also from apoptosis. that the acute signal the two receptor is essential for a We that activity NF-κB activity and the of IκB expression for signals transient NF-κB activity (9Wajant H. 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Rev. 1: Scholar, Microbiol. 2002; Scholar, J. J. P. G. J. Neurosci. 2001; Scholar, G. Kollias G. J. 2001; Scholar). The TNF transgenic described that neuronal TNF expression is a not To the the of primary neurons from these mice that TNF expression the neurons toward to excitotoxic for the in vivo of a neuroprotective pathway was previously obtained by in a model of retinal ischemia (10Fontaine V. Mohand-Said S. Hanoteau N. Fuchs C. Pfizenmaier K. Eisel U. J. Neurosci. 2002; 22: 1-7Google Scholar). We have in a model of cerebral ischemia that transgenic mice as with wild type L. M. Eisel and H. In data that TNF neuroprotection via TNFR2 and that NMDAR and the role of TNF in the We that TNF functions as an in the with differential signaling through the two its to and Thus, on the type and of disease, cellular of the and of signaling components, TNF function to or A of the differential signals that initiated by TNFR1 and TNFR2 in neurons and of with pathways that for neuronal is essential in to we that triggering of TNFR2 be a in neurodegenerative diseases because induces an anti-apoptotic in neurons by action with receptor be for in with or of with signal pathways. We for the TNFR1 and TNFR2 mice. We for with murine and TNFR2-specific We for and for with and for the