Irish Journal of Medical Science

, Volume 182, Issue 2, pp 157–162 | Cite as

Targeting tumour necrosis factor-α in hypoxia and synaptic signalling

  • J. J. O’Connor
Review Article


Tumour necrosis factor (TNF)-α is a pro-inflammatory cytokine, which is synthesised and released in the brain by astrocytes, microglia and neurons in response to numerous internal and external stimuli. It is involved in many physiological and pathophysiological processes such as gene transcription, cell proliferation, apoptosis, synaptic signalling and neuroprotection. The complex actions of TNF-α in the brain are under intense investigation. TNF-α has the ability to induce selective necrosis of some cells whilst sparing others and this has led researchers to discover multiple activated signalling cascades. In many human diseases including acute stroke and inflammation and those involving hypoxia, levels of TNF-α are increased throughout different brain regions. TNF-α signalling may also have several positive and negative effects on neuronal function including glutamatergic synaptic transmission and plasticity. Exogenous TNF-α may also exacerbate the neuronal response to hypoxia. This review will summarise the actions of TNF-α in the central nervous system on synaptic signalling and its effects during hypoxia.


TNF-α Hypoxia Prolyl hydroxylase Hippocampus Synaptic transmission Synaptic plasticity Inflammation 



I would like to thank Gatambwa Mukandala for help with the production of the figures. This work was supported in part by funding from Science Foundation Ireland (SFI; 09/RFP/NES2450).

Conflict of interest



  1. 1.
    Carswell EA, Old LJ, Kassel RL (1975) An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 72:3666–3670CrossRefPubMedGoogle Scholar
  2. 2.
    Lieberman AP, Pitha PM, Shin HS et al (1989) Production of tumor necrosis factor and other cytokines by astrocytes stimulated with lipopolysaccharide or a neurotropic virus. Proc Natl Acad Sci USA 86:6348–6352CrossRefPubMedGoogle Scholar
  3. 3.
    Cacci E, Claasen JH, Kokaia Z (2005) Microglia-derived tumor necrosis factor-alpha exaggerates death of newborn hippocampal progenitor cells in vitro. J Neurosci Res 80:789–797CrossRefPubMedGoogle Scholar
  4. 4.
    Kogo J, Takeba Y, Kumai T et al (2006) Involvement of TNF-α in glutamate-induced apoptosis in a differentiated neuronal cell line. Brain Res 1122:201–208CrossRefPubMedGoogle Scholar
  5. 5.
    Tchelingerian JL, Le Saux F, Jacque C (1996) Identification and topography of neuronal cell populations expressing TNF alpha and IL-1 alpha in response to hippocampal lesion. J Neurosci Res 43:99–106CrossRefPubMedGoogle Scholar
  6. 6.
    Black RA, Rauch CT, Kozlosky CJ et al (1997) A metalloproteinase disintegrin that releases tumour-necrosis factor-[alpha] from cells. Nature 385:729–733CrossRefPubMedGoogle Scholar
  7. 7.
    Jelinek DF, Lipsky PE (1987) Enhancement of human B cell proliferation and differentiation by tumor necrosis factor-alpha and interleukin 1. J Immunol 139:2970–2976PubMedGoogle Scholar
  8. 8.
    Murphy M, Perussia B, Trinchieri G (1988) Effects of recombinant tumor necrosis factor, lymphotoxin, and immune interferon on proliferation and differentiation of enriched hematopoietic precursor cells. Exp Hematol 16:131–138PubMedGoogle Scholar
  9. 9.
    Collins T, Lapierre LA, Fiers W (1986) Recombinant human tumor necrosis factor increases mRNA levels and surface expression of HLA-A, B antigens in vascular endothelial cells and dermal fibroblasts in vitro. Proc Natl Acad Sci USA 83:446–450CrossRefPubMedGoogle Scholar
  10. 10.
    Grilli M, Chen-Tran A, Lenardo MJ (1993) Tumor necrosis factor alpha mediates a T cell receptor-independent induction of the gene regulatory factor NF-kappa B in T lymphocytes. Mol Immunol 30:1287–1294CrossRefPubMedGoogle Scholar
  11. 11.
    Wilde GJ, Pringle AK, Sundstrom LE et al (2000) Attenuation and augmentation of ischaemia-related neuronal death by tumour necrosis factor-alpha in vitro. Eur J Neurosci 12:3863–3870CrossRefPubMedGoogle Scholar
  12. 12.
    Ginis I, Jaiswal R, Klimanis D et al (2002) TNF-α-induced tolerance to ischemic injury involves differential control of NF-kappaB transactivation: the role of NF-kappaB association with p300 adaptor. J Cereb Blood Flow Metab 22:142–152CrossRefPubMedGoogle Scholar
  13. 13.
    Bessler H, Djaldetti R, Salman H et al (1999) IL-1 beta, IL-2, IL-6 and TNF-α production by peripheral blood mononuclear cells from patients with Parkinson’s disease. Biomed Pharmacother 53:141–145CrossRefPubMedGoogle Scholar
  14. 14.
    Goodman JC, Robertson CS, Grossman RG et al (1990) Elevation of tumor necrosis factor in head injury. J Neuroimmunol 30:213–217CrossRefPubMedGoogle Scholar
  15. 15.
    Hofman FM, Hinton DR, Johnson K et al (1989) Tumor necrosis factor identified in multiple sclerosis brain. J Exp Med 170:607–612CrossRefPubMedGoogle Scholar
  16. 16.
    Liu T, Clark RK, Mcdonnell PC et al (1994) Tumor necrosis factor-alpha expression in ischemic neurons. Stroke 25:1481–1488CrossRefPubMedGoogle Scholar
  17. 17.
    Musumeci G, Grasselli G, Rossi S et al (2011) Transient receptor potential vanilloid 1 channels modulate the synaptic effects of TNF-α and of IL-1β in experimental autoimmune encephalomyelitis. Neurobiol Dis 43:669–677CrossRefPubMedGoogle Scholar
  18. 18.
    Pickering M, Cumiskey D, O’Connor JJ (2005) Actions of TNF-α on glutamatergic synaptic transmission in the central nervous system. Exp Physiol 90:663–670CrossRefPubMedGoogle Scholar
  19. 19.
    Pickering M, O’Connor JJ (2007) Pro-inflammatory cytokines and their effects in the dentate gyrus. Prog Brain Res 163:339–354CrossRefPubMedGoogle Scholar
  20. 20.
    Dziewulska D, Mossakowski MJ (2003) Cellular expression of tumor necrosis factor a and its receptors in human ischemic stroke. Clin Neuropathol 22:35–40PubMedGoogle Scholar
  21. 21.
    Figiel I, Dzwonek K (2007) TNF[alpha] and TNF receptor 1 expression in the mixed neuronal-glial cultures of hippocampal dentate gyrus exposed to glutamate or trimethyltin. Brain Res 1131:17–28CrossRefPubMedGoogle Scholar
  22. 22.
    Dopp JM, Mackenzie-Graham A, Otero GC et al (1997) Differential expression, cytokine modulation, and specific functions of type-1 and type-2 tumor necrosis factor receptors in rat glia. J Neuroimmunol 75:104–112CrossRefPubMedGoogle Scholar
  23. 23.
    Bebo B, Linthicum DS (1995) Expression of mRNA for 55-kDa and 75-kDa tumor necrosis factor (TNF) receptors in mouse cerebrovascular endothelium: effects of interleukin-1 beta, interferon-gamma and TNF-α on cultured cells. J Neuroimmunol 62:161–167CrossRefPubMedGoogle Scholar
  24. 24.
    Tartaglia LA, Weber RF, Figari IS et al (1991) The two different receptors for tumor necrosis factor mediate distinct cellular responses. Proc Natl Acad Sci USA 88:9292–9296CrossRefPubMedGoogle Scholar
  25. 25.
    Chen G, Goeddel DV (2002) TNF-R1 signaling: a beautiful pathway. Science 296:1634–1635CrossRefPubMedGoogle Scholar
  26. 26.
    Schneider-Brachert W, Tchikov V, Neumeyer J et al (2004) Compartmentalization of TNF receptor 1 signaling: internalized TNF receptosomes as death signaling vesicles. Immunity 21:415–428CrossRefPubMedGoogle Scholar
  27. 27.
    Marchetti L, Klein M, Schlett K et al (2004) Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-methyl-d-aspartate receptor activation. Essential role of a TNF receptor 2-mediated phosphatidylinositol 3-kinase-dependent NF-kappa B pathway. J Biol Chem 279:32869–32881CrossRefPubMedGoogle Scholar
  28. 28.
    MacEwan DJ (2002) TNF receptor subtype signalling: differences and cellular consequences. Cell Signal 14:477–492CrossRefPubMedGoogle Scholar
  29. 29.
    Beattie EC, Stellwagen D, Morishita W et al (2002) Control of synaptic strength by glial TNF-α. Science 295:2282–2285CrossRefPubMedGoogle Scholar
  30. 30.
    Furukawa K, Mattson MP (1998) The transcription factor NF-kappaB mediates increases in calcium currents and decreases in NMDA- and AMPA/kainate-induced currents induced by tumor necrosis factor-alpha in hippocampal neurons. J Neurochem 70:1876–1886CrossRefPubMedGoogle Scholar
  31. 31.
    Stellwagen D, Malenka RC (2006) Synaptic scaling mediated by glial TNF-α. Nature 440:1054–1059CrossRefPubMedGoogle Scholar
  32. 32.
    Stellwagen D, Beattie EC, Seo JY et al (2005) Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci 25:3219–3228CrossRefPubMedGoogle Scholar
  33. 33.
    Stellwagen D (2011) The contribution of TNFα to synaptic plasticity and nervous system function. Adv Exp Med Biol 691:541–557CrossRefPubMedGoogle Scholar
  34. 34.
    He P, Liu Q, Wu J et al (2012) Genetic deletion of TNF receptor suppresses excitatory synaptic transmission via reducing AMPA receptor synaptic localization in cortical neurons. FASEB J 26:334–345CrossRefPubMedGoogle Scholar
  35. 35.
    Watters O, Pickering M, O’Connor JJ (2011) Preconditioning effects of tumor necrosis factor-α and glutamate on calcium dynamics in rat organotypic hippocampal cultures. J Neuroimmunol 234:27–39CrossRefPubMedGoogle Scholar
  36. 36.
    Santello M, Bezzi P, Volterra A (2011) TNFα controls glutamatergic gliotransmission in the hippocampal dentate gyrus. Neuron 69:988–1001CrossRefPubMedGoogle Scholar
  37. 37.
    Tancredi V, D’Arcangelo G, Grassi F et al (1992) Tumor necrosis factor alters synaptic transmission in rat hippocampal slices. Neurosci Lett 146:176–178CrossRefPubMedGoogle Scholar
  38. 38.
    Cunningham AJ, Murray CA, O’Neill LAJ et al (1996) IL-1b and tumour necrosis factor-a inhibit LTP in the rat dentate gyrus in vitro. Neurosci Lett 203:17–20CrossRefPubMedGoogle Scholar
  39. 39.
    Butler M, O’Connor JJ, Moynagh P (2004) Dissection of TNF-α inhibition of LTP reveals a p38 MAPK-dependent mechanism which maps to early but not late-phase LTP. Neuroscience 124:319–326CrossRefPubMedGoogle Scholar
  40. 40.
    Curran BP, Murray H, O’Connor JJ (2003) A role for c-jun n-terminal kinase in the inhibition of long-term potentiation by IL-1b and long-term depression in the rat dentate gyrus in vitro. Neuroscience 118:347–357CrossRefPubMedGoogle Scholar
  41. 41.
    Coogan A, O’Neill LAJ, O’Connor JJ (1999) The p38 MAP kinase inhibitor SB203580 antagonises the inhibitory effect of interleukin-1b on long-term potentiation in the rat dentate gyrus in vitro. Neuroscience 93:57–69CrossRefPubMedGoogle Scholar
  42. 42.
    Curran B, O’Connor JJ (2001) The pro-inflammatory cytokine interleukin-18 impairs long-term potentiation and NMDA receptor-mediated transmission in the rat hippocampus in vitro. Neuroscience 108:83–90CrossRefPubMedGoogle Scholar
  43. 43.
    Curran B, O’Connor JJ (2003) The inhibition of long-term potentiation by pro-inflammatory cytokines is attenuated in the presence of nicotine. Neurosci Lett 344:103–106CrossRefPubMedGoogle Scholar
  44. 44.
    Cumiskey D, Butler MP, Moynagh PN et al (2006) Evidence for a role for the group 1 metabotropic glutamate receptor in the inhibitory effect of tumour necrosis factor-α on long-term potentiation. Brain Res 1136:13–19CrossRefGoogle Scholar
  45. 45.
    Albensi BC, Mattson MP (2000) Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticity. Synapse 35:151–159CrossRefPubMedGoogle Scholar
  46. 46.
    Perea G, Araque A (2005) Synaptic regulation of the astrocyte calcium signal. J Neural Transm 112:127–135CrossRefPubMedGoogle Scholar
  47. 47.
    Ikeda E (2005) Cellular response to tissue hypoxia and its involvement in disease progression. Pathol Int 55:603–610CrossRefPubMedGoogle Scholar
  48. 48.
    Ratan RR, Siddiq A, Smirnova N et al (2007) Harnessing hypoxic adaptation to prevent, treat, and repair stroke. J Mol Med 85:1331–1338CrossRefPubMedGoogle Scholar
  49. 49.
    Trincavelli ML, Marroni M, Tuscano D et al (2004) Regulation of A2B adenosine receptor functioning by tumour necrosis factor a in human astroglial cells. J Neurochem 91:1180–1190CrossRefPubMedGoogle Scholar
  50. 50.
    Trincavelli ML, Tonazzini I, Montali M et al (2008) Short-term TNF-alpha treatment induced A2B adenosine receptor desensitization in human astroglial cells. J Cell Biochem 104:150–161CrossRefPubMedGoogle Scholar
  51. 51.
    Row BW, Liu R, Xu W et al (2003) Intermittent hypoxia is associated with oxidative stress and spatial learning deficits in the rat. Am J Respir Crit Care Med 167:1548–1553CrossRefPubMedGoogle Scholar
  52. 52.
    Zhan G, Serrano F, Fenik P et al (2005) NADPH oxidase mediates hypersomnolence and brain oxidative injury in a murine model of sleep apnoea. Am J Respir Crit Care Med 172:921–929CrossRefPubMedGoogle Scholar
  53. 53.
    Tam CS, Wong M, Tam K et al (2007) The effect of acute intermittent hypercapnic hypoxia treatment on IL-6, TNF-α, and CRP levels in piglets. Sleep 30:723–727PubMedGoogle Scholar
  54. 54.
    Ryan S, Taylor CT, McNicholas WT (2006) Predictors of elevated nuclear factor-kappaB-dependent genes in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 174:824–830CrossRefPubMedGoogle Scholar
  55. 55.
    Savransky V, Bevans S, Nanayakkara A et al (2007) Chronic intermittent hypoxia causes hepatitis in a mouse model of diet-induced fatty liver. Am J Physiol Gastrointest Liver Physiol 293:G871–G877CrossRefPubMedGoogle Scholar
  56. 56.
    Bullock R, Zauner A, Woodward J et al (1995) Massive persistent release of excitatory amino acids following human occlusive stroke. Stroke 26:2187–2189CrossRefPubMedGoogle Scholar
  57. 57.
    Bruce AJ, Boling W, Kindy MS et al (1996) Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat Med 2:788–794CrossRefPubMedGoogle Scholar
  58. 58.
    Burkovetskaya ME, Levin SG, Godukhin OV (2007) Neuroprotective effects of interleukin-10 and tumor necrosis factor-alpha against hypoxia-induced hyperexcitability in hippocampal slice neurons. Neurosci Lett 416:236–240CrossRefPubMedGoogle Scholar
  59. 59.
    Zhou J, Fandrey J, Schümann J et al (2003) NO and TNF-α released from activated macrophages stabilize HIF-1alpha in resting tubular LLC-PK1 cells. Am J Physiol Cell Physiol 284:C439–C446PubMedGoogle Scholar
  60. 60.
    Jung Y, Isaacs JS, Lee S et al (2003) Hypoxia-inducible factor induction by tumour necrosis factor in normoxic cells requires receptor-interacting protein-dependent nuclear factor kappa B activation. Biochem J 370:1011–1017CrossRefPubMedGoogle Scholar
  61. 61.
    Goel G, Guo M, Ding J et al (2010) Combined effect of tumor necrosis factor (TNF)-alpha and heat shock protein (HSP)-70 in reducing apoptotic injury in hypoxia: a cell culture study. Neurosci Lett 483:162–166CrossRefPubMedGoogle Scholar
  62. 62.
    Badiola N, Malagelada C, Llecha N et al (2009) Activation of caspase-8 by tumour necrosis factor receptor 1 is necessary for caspase-3 activation and apoptosis in oxygen-glucose deprived cultured cortical cells. Neurobiol Dis 35:438–447CrossRefPubMedGoogle Scholar
  63. 63.
    Echeverry R, Wu F (2012) Haile WB (2012) The cytokine tumor necrosis factor-like weak inducer of apoptosis and its receptor fibroblast growth factor-inducible 14 have a neuroprotective effect in the central nervous system. J Neuroinflammation 9:45CrossRefPubMedGoogle Scholar
  64. 64.
    Batti L, O’Connor JJ (2010) Tumor necrosis factor-α impairs the recovery of synaptic transmission from hypoxia in rat hippocampal slices. J Neuroimmunol 218:21–27CrossRefPubMedGoogle Scholar
  65. 65.
    Corcoran A, O’Connor JJ (2010) The effects of hypoxia, prolyl hydroxylase inhibition and TNF-α on synaptic transmission in the rat hippocampus. Proc Br Pharm Soc Winter Meet 8(1):157Google Scholar
  66. 66.
    Wall AM, O’Connor JJ (2011) Acute hypoxia impairs the recovery of synaptic transmission in the rat dentate gyrus and potentiates long-term potentiation in the presence of tumour necrosis factor-α and picrotoxin. Ir J Med Sci 180(Suppl 2):56Google Scholar

Copyright information

© Royal Academy of Medicine in Ireland 2013

Authors and Affiliations

  1. 1.UCD School of Biomolecular and Biomedical ScienceConway Institute of Biomolecular and Biomedical Research, University College Dublin, BelfieldDublin 4Ireland

Personalised recommendations