We are grateful to Prof. E. N. Benveniste for providing cDNA for a partial TNF-α. We thank Ms. Yasuko Takeuchi, Ms. Mayumi Sora, and Mr. Tomohisa Suzuki for their technical assistance, Dr. Faiz Kermani for his helpful comments, and the Research Center for Molecular Medicine, Hiroshima University School of Medicine, for the use of its facilities. This study was supported by Grant-in-Aid 11670089 from the Ministry of Education, Science and Culture, Japan and partly supported by the Promotion of Fundamental Studies in Health Science of the Organization for Pharmaceutical Safety and Research.

  • 1
    Alessi D.R., Cuenda A., Cohen P., Dudley D.T., Saltiel A.R. (1995) PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase in vitro and in vivo.J. Biol. Chem. 270 2748927494.
  • 2
    Barger S.W., Horster D., Furukawa K., Goodman Y., Krieglstein J., Mattson M.P. (1995) Tumor necrosis factors α and β protect neurons against amyloid β-peptide toxicity: evidence for involvement of a κB-binding factor and attenuation of peroxide and Ca2+ accumulation.Proc. Natl. Acad. Sci. USA 92 93289332.
  • 3
    Baumgartner R.A., Yamada K., Deramo V.A., Beaven M.A. (1994) Secretion of TNF from a rat mast cell line is a brefeldin A-sensitive and a calcium/protein kinase C-regulated process.J. Immunol. 153 26092617.
  • 4
    Bhat N.R., Zhang P., Lee J.C., Hogan E.L. (1998) Extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor-α gene expression in endotoxin-stimulated primary glial cultures.J. Neurosci. 18 16331641.
  • 5
    Brosnan C.F., Selmaj K., Raine C.S. (1988) Hypothesis: a role for tumor necrosis factor in immune-mediated demyelination and its relevance to multiple sclerosis.J. Neuroimmunol. 18 8794.
  • 6
    Bruce A.J., Boling W., Kindy M.S., Peschon J., Kraemer P.J., Carpenter M.K., Holtsberg F.W., Mattson M.P. (1996) Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors.Nat. Med. 2 788794.
  • 7
    Cheng B., Christakos S., Mattson M.P. (1994) Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis.Neuron 12 139153.
  • 8
    Chiozzi P., Murgia M., Falzoni S., Ferrari D., Di Virgilio F. (1996) Role of the P2z receptor in spontaneous cell death in J774 macrophage culture.Biochem. Biophys. Res. Commun. 218 176181.
  • 9
    Chomczynski P. & Sacchi N. (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.Anal. Biochem. 162 156159.
  • 10
    Chung I.L., Kwon J., Benveniste E.N. (1992) Role of protein kinase C activity in tumor necrosis factor-α gene expression: involvement at the transcription level.J. Immunol. 149 39843902.
  • 11
    Cockcroft S. & Gomperts B.D. (1979) ATP induces nucleotide permeability in rat mast cells.Nature 279 541542.
  • 12
    Dickson D.W., Mattiace L.A., Kure K., Hutchins K., Lyman W.D., Brosnan C.F. (1991) Microglia in human disease, with an emphasis on acquired immune deficiency syndrome.Lab. Invest. 64 135156.
  • 13
    Di Virgilio F. (1995) The P2Z purinoceptor: an intriguing role in immunity, inflammation and cell death.Immunol. Today 16 524528.
  • 14
    Drapier J.C., Wietzerbin J., Hibbs J.B.J r. (1988) Interferon-γ and tumor necrosis factor induce the L-arginine-dependent cytotoxic effector mechanism in murine macrophages.Eur. J. Immunol. 18 15871592.
  • 15
    Dudley D.T., Pang L., Decker S.J., Bridges A.J., Saltiel A.R. (1995) A synthetic inhibitor of the mitogen-activated protein kinase cascade.Proc. Natl. Acad. Sci. USA 92 76867689.
  • 16
    Ferrari D., Villalba M., Chiozzi P., Falzoni S., Ricciardi-Castagnoli P., Di Virgilio F. (1996) Mouse microglia cells express a plasma membrane pore gated by extracellular ATP.J. Immunol. 156 15311539.
  • 17
    Ferrari D., Chiozzi P., Falzoni S., Dal Susino M., Melchiorri L., Baricordi O.R., Di Virgilio F. (1997a) Extracellular ATP triggers IL-1β release by activating the purinergic P2z receptor of human macrophages.J. Immunol. 159 14511458.
  • 18
    Ferrari D., Chiozzi P., Simonetta F., Hanau S., Di Virgilio F. (1997b) Purinergic modulation of interleukin-1β release from microglial cells stimulated with bacterial endotoxin.J. Exp. Med. 185 579582.
  • 19
    Ferrari D., Chiozzi P., Falzoni S., Dal Susino M., Collo G., Buell G., Di Virgilio F. (1997c) ATP-mediated cytotoxicity in microglial cells.Neuropharmacology 36 12951301.
  • 20
    Ferrari D., Wesselborg S., Bauer M.K.A., Schulze-Osthoff K. (1997d) Extracellular ATP activates transcription factor NF-κB through the P2Z purinoreceptor by selectively targeting NF-κB p65 (Re1A). J. Cell Biol. 139 16351643.
  • 21
    Ferrari D., Los M., Bauer B.K., Vandenabeele P., Wesselborg S., Schulze-Osthoff K. (1999a) P2Z purinoreceptor ligation induces activation of caspases with distinct roles in apoptotic and necrotic alterations of cell death.FEBS Lett. 447 7175.
  • 22
    Ferrari D., Stroh C., Schulze-Osthoff K. (1999b) P2X7/P2Z purinoceptor-mediated activation of transcription factor NFAT in microglial cells. J. Biol. Chem. 274 1320513210.
  • 23
    Fillit H., Ding W.H., Buce L., Kalman J., Altstie L., Lawlor B., Wolf-Klein G. (1991) Elevated circulating tumor necrosis factor levels in Alzheimer's disease.Neurosci. Lett. 129 318320.
  • 24
    Gary D.S., Bruce-Keller A.J., Kindy M.S., Mattson M.P. (1998) Ischemic and excitotoxic brain injury is enhanced in mice lacking the p55 tumor necrosis factor receptor.J. Cereb. Blood Flow Metab. 18 12831287.
  • 25
    Hide I., Toriu N., Nuibe T., Inoue A., Hide M., Yamamoto S., Nakata Y. (1997) Suppression of TNF-α secretion by azelastine in a rat mast (RBL-2H3) cell line.J. Immunol. 159 29322940.
  • 26
    Inoue K. (1998) The function of ATP receptors in the hippocampus.Pharmacol. Res. 38 323331.
  • 27
    Inoue K., Koizumi S., Nakazawa K., Hamanoue M., Kohsaka S. (1994) Modulatory effect of plasminogen on NMDA-induced increase in intracellular free calcium concentration in rat cultured hippocampal neurones.Neurosci. Lett. 179 8790.
  • 28
    Inoue K., Nakajima K., Morimoto T., Kikuchi Y., Koizumi S., Illes P., Kohsaka S. (1998) ATP stimulation of Ca2+-dependent plasminogen release from culture microglia. Br. J. Pharmacol. 123 13041310.
  • 29
    Kreutzberg G.W. (1996) Microglia: a sensor for pathological events in the CNS.Trends Neurosci. 19 312318.
  • 30
    Langosch J.M., Gebicke-Haerter P.J., Nörenberg W., Illes P. (1994) Characterization and transduction mechanisms of purinoreceptors in activated rat microglia.Br. J. Pharmacol. 113 2934.
  • 31
    Lee J.C., Laydon J.T., McDonnell P.C., Gallagher T.F., Kumar S., Green D., McNulty D., Blumenthal M.J., Heys J.R., Landvatter S.W., Stickler J.E., McLaughlin M.M., Siemens I.R., Fisher S.M., Livi G.P., Adams J.L., Young P.R. (1994) A protein kinase involved in the regulation of inflammatory cytokine biosynthesis.Nature 372 739746.
  • 32
    Markwardt F., Löhn M., Böhm T., Klapperstück M. (1997) Purinoceptor-operated cationic channels in human B lymphocytes.J. Physiol. (Lond.) 498 143151.
  • 33
    Merrill J.E. & Benveniste E.N. (1996) Cytokines in inflammatory brain lesions: helpful and harmful.Trends Neurosci. 19 331338.
  • 34
    Murgia M., Hanau S., Pizzo P., Rippa M., Di Virgilio F. (1993) Oxidized ATP: an irreversible inhibitor of the macrophage purinergic P2Z receptor.J. Biol. Chem. 268 81998203.
  • 35
    Nakajima K., Hamanoue M., Shimojo M., Takei N., Kohsaka S. (1989) Characterization of microglia isolated from a primary culture of embryonic rat brain by a simplified method.Biomed. Res. 10 411423.
  • 36
    Nakajima K., Shimojo M., Hamanoue M., Ishiura S., Sugita H., Kohsaka S. (1992) Identification of elastase as a secretory protease from cultured rat microglia.J. Neurochem. 58 14011408.
  • 37
    Neary J.T., Kang Y., Bu Y., Yu E., Akong K., Peters C.M. (1999) Mitogenic signaling by ATP/P2Y purinergic receptors in astrocytes: involvement of a calcium-independent protein kinase C, extracellular signal-regulated protein kinase pathway distinct from the phosphatidylinositol-specific phospholipase C/calcium pathway.J. Neurosci. 19 42114220.
  • 38
    Nörenberg W., Langosch J.M., Gebicke-Haerter P.J., Illes P. (1994) Characterization and possible function of adenosine 5-triphosphate receptors in activated rat microglia.Br. J. Pharmacol. 111 942950.
  • 39
    Nörenberg W., Cordes A., Blohbaum G., Froflich R., Illes P. (1997) Coexistence of purino- and pyrimidinoceptors on activated rat microglial cells.Br. J. Pharmacol. 121 10871098.
  • 40
    Perry V.H. & Gordon S. (1988) Macrophages and microglia in the nervous system.Trends Neurosci. 11 273277.
  • 41
    Pyo H., Jou I., Jung S., Hong S., Joe E. -H. (1998) Mitogen-activated protein kinases activated by lipopolysaccharide and β-amyloid in cultured rat microglia. Neuroreport 9 871874.
  • 42
    Ralevic V. & Burnstock G. (1998) Receptors for purines and pyrimidines.Pharmacol. Rev. 50 413492.
  • 43
    Robinson M.J. & Cobb M.H. (1997) Mitogen-activated protein kinase pathways.Curr. Opin. Cell Biol. 9 180186.
  • 44
    Shen Y., Li R., Shiosaki K. (1997) Inhibition of p75 tumor necrosis factor receptor by antisense oligonucleotides increases hypoxic injury and β-amyloid toxicity in human neuronal cell line. J. Biol. Chem. 272 35503553.
  • 45
    Surprenant A., Rassendren F., Kawashima E., North R.A., Buell G. (1996) The cytolytic P2Z receptor for extracellular ATP identified ATP as a P2X receptor (P2X7). Science 272 735738.
  • 46
    Van Antwerp D.J., Martin S.J., Verma I.M., Green D.R. (1998) Inhibition of TNF-induced apoptosis by NF-κB. Trends Cell Biol. 8 107111.
  • 47
    Walton K.M., DiRocco R.D., Bartlett B.A., Koury E., Marcy V.R., Jarvis B., Schaefer E.M., Bhat R.V. (1998) Activation of p38MAPK in microglia after ischemia.J. Neurochem. 70 17641767.
  • 48
    Walz W., Ilschner S., Ohleneyer C., Banati R., Kettenmann H. (1993) Extracellular ATP activates a cation concentration and a K+ conductance in cultured microglial cells from mouse brain.Neuroscience 13 44034411.