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The many faces of tumor necrosis factor in stroke

Nature Medicine volume 8, pages 1363–1368 (2002)Cite this article

The cytokine, TNF, participates in virtually every aspect of stroke. Its effects, however, often appear contradictory. Analysis of the current model for TNF receptor signaling and TNF interactions with other stroke mediators helps to resolve some of these apparent discrepancies.

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Figure 1: The core signaling framework for TNFR1 showing pathways that subserve inflammation, immune modulation and apoptosis4,5,74,75,76.
Figure 2: The TNF signalsome converted into a simplified 'scales of cell death/cell survival' model (with TRADD as the crosspiece of the balance) to illustrate diverse TNFR1 signaling functions.
Figure 3: General overview of the roles of TNF-α in stroke.

References

  1. Oppenheim, J.J. Cytokines: Past, present, and future. Int. J. Hematol. 74, 3–8 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Szelenyi, J. Cytokines and the central nervous system. Brain Res. Bull 54, 329–338 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Inglot, A.D. Classification of cytokines according to the receptor code. Arch. Immunol. Ther. Exp. (Warsz.) 45, 353–357 (1997).

    CAS  Google Scholar 

  4. Liu, Z.G., Hsu, H., Goeddel, D.V. & Karin, M. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF—κB activation prevents cell death. Cell 87, 565–576 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Chen, G. & Goeddel, D.V. TNF-R1 signaling: a beautiful pathway. Science 296, 1634–1635 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Wallach, D. et al. How are the regulators regulated? The search for mechanisms that impose specificity on induction of cell death and NF-κB activation by members of the TNF/NGF receptor family. Arthritis Res. 4, S189–196 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Pimentel-Muinos, F.X. & Seed, B. Regulated commitment of TNF receptor signaling: a molecular switch for death or activation. Immunity 11, 783–793 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Black, R.A. et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature 385, 729–733 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Chan, F.K. et al. A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science 288, 2351–2354 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Heyninck, K. & Beyaert, R. Crosstalk between NF-κB-activating and apoptosis-inducing proteins of the TNF-receptor complex. Mol. Cell Biol. Res. Commun 4, 259–265 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Segui, B. et al. Involvement of FAN in TNF-induced apoptosis. J. Clin. Invest. 108, 143–151 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kolesnick, R.N. & Kronke, M. Regulation of ceramide production and apoptosis. Annu. Rev. Physiol. 60, 643–665 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Cutler, R.G. & Mattson, M.P. Sphingomyelin and ceramide as regulators of development and lifespan. Mech. Ageing Dev. 122, 895–908 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Gourin, C.G. & Shackford, S.R. Production of tumor necrosis factor-α and interleukin-1β by human cerebral microvascular endothelium after percussive trauma. J. Trauma 42, 1101–1107 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Pober, J.S. & Cotran, R.S. Cytokines and endothelial cell biology. Physiol. Rev. 70, 427–451 (1990).

    Article  CAS  PubMed  Google Scholar 

  16. Hummel, V. et al. Production of MMPs in human cerebral endothelial cells and their role in shedding adhesion molecules. J. Neuropathol. Exp. Neurol. 60, 320–327 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Mark, K.S., Trickler, W.J. & Miller, D.W. Tumor necrosis factor-α induces cyclooxygenase-2 expression and prostaglandin release in brain microvessel endothelial cells. J. Pharmacol. Exp. Ther. 297, 1051–1058 (2001).

    CAS  PubMed  Google Scholar 

  18. Terry, C.M., Clikeman, J.A., Hoidal, J.R. & Callahan, K.S. TNF-α and IL-1α induce heme oxygenase-1 via protein kinase C, Ca2+, and phospholipase A2 in endothelial cells. Am. J. Physiol. 276, H1493–1501 (1999).

    CAS  PubMed  Google Scholar 

  19. Weber, C. et al. Antioxidants inhibit monocyte adhesion by suppressing nuclear factor-κ B mobilization and induction of vascular cell adhesion molecule-1 in endothelial cells stimulated to generate radicals. Arterioscler. Thromb. 14, 1665–1673 (1994).

    Article  CAS  PubMed  Google Scholar 

  20. Plutzky, J. Inflammatory pathways in atherosclerosis and acute coronary syndromes. Am. J. Cardiol. 88, 10K–15K (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Choy, J.C., Granville, D.J., Hunt, D.W. & McManus, B.M. Endothelial cell apoptosis: biochemical characteristics and potential implications for atherosclerosis. J. Mol. Cell. Cardiol. 33, 1673–1690 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Tipping, P.G. & Hancock, W.W. Production of tumor necrosis factor and interleukin-1 by macrophages from human atheromatous plaques. Am. J. Pathol. 142, 1721–1728 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Weyand, C.M. et al. T-cell immunity in acute coronary syndromes. Mayo Clin. Proc. 76, 1011–1020 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Bryl, E., Vallejo, A.N., Weyand, C.M. & Goronzy, J.J. Down-regulation of cd28 expression by tnf-α. J. Immunol. 167, 3231–3238 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Ruetzler, C.A., Furuya, K., Takeda, H. & Hallenbeck, J.M. Brain vessels normally undergo cyclic activation and inactivation: Evidence from tumor necrosis factor-α, heme oxygenase-1, and manganese superoxide dismutase immunostaining of vessels and perivascular brain cells. J. Cereb. Blood Flow Metab. 21, 244–252 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Hallenbeck, J.M. et al. Stroke risk factors prepare rat brainstem tissues for modified local Shwartzman reaction. Stroke 19, 863–869 (1988).

    Article  CAS  PubMed  Google Scholar 

  27. Becher, H., Grau, A., Steindorf, K., Buggle, F. & Hacke, W. Previous infection and other risk factors for acute cerebrovascular ischaemia: Attributable risks and the characterisation of high risk groups. J. Epidemiol. Biostat. 5, 277–283 (2000).

    CAS  PubMed  Google Scholar 

  28. Siren, A.L. et al. Proinflammatory cytokine expression contributes to brain injury provoked by chronic monocyte activation. Mol. Med. 7, 219–229 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Takeda, H. et al. Induction of mucosal tolerance to E-selectin prevents ischemic and hemorrhagic stroke in spontaneously hypertensive genetically stroke-prone rats. Stroke (expedited publication; in the press).

  30. Dirnagl, U., Iadecola, C. & Moskowitz, M.A. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 22, 391–397 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Neumar, R.W. Molecular mechanisms of ischemic neuronal injury. Ann. Emerg. Med. 36, 483–506 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Paschen, W. & Frandsen, A. Endoplasmic reticulum dysfunction—a common denominator for cell injury in acute and degenerative diseases of the brain? J. Neurochem 79, 719–725 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Botchkina, G.I., Meistrell, M.E., 3rd, Botchkina, I.L. & Tracey, K.J. Expression of TNF and TNF receptors (p55 and p75) in the rat brain after focal cerebral ischemia. Mol. Med. 3, 765–781 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu, T. et al. Tumor necrosis factor-α expression in ischemic neurons. Stroke 25, 1481–1488 (1994).

    Article  CAS  PubMed  Google Scholar 

  35. Earnshaw, W.C., Martins, L.M. & Kaufmann, S.H. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu. Rev. Biochem. 68, 383–424 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Hsu, H., Shu, H.B., Pan, M.G. & Goeddel, D.V. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 84, 299–308 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. Venters, H.D. et al. A new mechanism of neurodegeneration: A pro-inflammatory cytokine inhibits receptor signaling by a survival peptide. Proc. Natl. Acad. Sci. USA 96, 9879–9884 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rabuffetti, M. et al. Inhibition of caspase-1-like activity by Ac-Tyr-Val-Ala-Asp-chloromethyl ketone induces long-lasting neuroprotection in cerebral ischemia through apoptosis reduction and decrease of pro-inflammatory cytokines. J. Neurosci. 20, 4398–4404 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chao, C.C., Hu, S. & Peterson, P.K. Glia, cytokines, and neurotoxicity. Crit. Rev. Neurobiol. 9, 189–205 (1995).

    CAS  PubMed  Google Scholar 

  40. Feuerstein, G., Wang, X. & Barone, F.C. Cytokines in brain ischemia—the role of TNF α. Cell. Mol. Neurobiol. 18, 695–701 (1998).

    CAS  PubMed  Google Scholar 

  41. Dawson, D.A., Martin, D. & Hallenbeck, J.M. Inhibition of tumor necrosis factor-α reduces focal cerebral ischemic injury in the spontaneously hypertensive rat. Neurosci. Lett. 218, 41–44 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Gregersen, R., Lambertsen, K. & Finsen, B. Microglia and macrophages are the major source of tumor necrosis factor in permanent middle cerebral artery occlusion in mice. J. Cereb. Blood Flow Metab. 20, 53–65 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Jander, S., Schroeter, M. & Stoll, G. Role of NMDA receptor signaling in the regulation of inflammatory gene expression after focal brain ischemia. J. Neuroimmunol. 109, 181–187 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Araki, E., Forster, C., Dubinsky, J.M., Ross, M.E. & Iadecola, C. Cyclooxygenase-2 inhibitor ns-398 protects neuronal cultures from lipopolysaccharide-induced neurotoxicity. Stroke 32, 2370–2375 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Nathan, C. & Xie, Q.W. Regulation of biosynthesis of nitric oxide. J. Biol. Chem. 269, 13725–13728 (1994).

    Article  CAS  PubMed  Google Scholar 

  46. Nogawa, S. et al. Interaction between inducible nitric oxide synthase and cyclooxygenase-2 after cerebral ischemia. Proc. Natl. Acad. Sci. USA 95, 10966–10971 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Rosenberg, G.A. et al. Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures. Brain Res. 893, 104–112 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Schlomann, U., Rathke-Hartlieb, S., Yamamoto, S., Jockusch, H. & Bartsch, J.W. Tumor necrosis factor α induces a metalloprotease-disintegrin, ADAM8 (CD 156): Implications for neuron-glia interactions during neurodegeneration. J. Neurosci. 20, 7964–7971 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Probert, L. et al. TNF-α transgenic and knockout models of CNS inflammation and degeneration. J. Neuroimmunol. 72, 137–141 (1997).

    Article  CAS  PubMed  Google Scholar 

  50. Marino, M.W. et al. Characterization of tumor necrosis factor-deficient mice. Proc. Natl. Acad. Sci. USA 94, 8093–8098 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Schreyer, S.A., Peschon, J.J. & LeBoeuf, R.C. Accelerated atherosclerosis in mice lacking tumor necrosis factor receptor p55. J. Biol. Chem. 271, 26174–26178 (1996).

    Article  CAS  PubMed  Google Scholar 

  52. Bruce, A.J. et al. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nature Med. 2, 788–794 (1996).

    Article  CAS  PubMed  Google Scholar 

  53. Shohami, E., Ginis, I. & Hallenbeck, J.M. Dual role of tumor necrosis factor α in brain injury. Cytokine Growth Factor Rev. 10, 119–130 (1999).

    Article  CAS  PubMed  Google Scholar 

  54. Martin-Villalba, A. et al. Therapeutic neutralization of CD95-ligand and TNF attenuates brain damage in stroke. Cell Death Differ. 8, 679–686 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Feldmann, M. Development of anti-TNF therapy for rheumatoid arthritis. Nature Rev. Immunol. 2, 364–371 (2002).

    Article  CAS  Google Scholar 

  56. TNF neutralization in MS: Results of a randomized, placebo-controlled multicenter study. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Neurology 53, 457–465 (1999).

  57. Zaremba, J. & Losy, J. Early TNF-α levels correlate with ischaemic stroke severity. Acta Neurol. Scand. 104, 288–295 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Sairanen, T. et al. Evolution of cerebral tumor necrosis factor-α production during human ischemic stroke. Stroke 32, 1750–1758 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Clark, W.M. & Lutsep, H.L. Potential of anticytokine therapies in central nervous system ischaemia. Expert Opin. Biol. Ther. 1, 227–237 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Schöbitz, B., De Kloet, E.R. & Holsboer, F. Gene expression and function of Interleukin 1, interleukin 6 and tumor necrosis factor in the brain. Prog. Neurobiol. 44, 397–432 (1994).

    Article  PubMed  Google Scholar 

  61. Wong, G.H. & Goeddel, D.V. Induction of manganous superoxide dismutase by tumor necrosis factor: possible protective mechanism. Science 242, 941–944 (1988).

    Article  CAS  PubMed  Google Scholar 

  62. Eddy, L.J., Goeddel, D.V. & Wong, G.H.W. Tumor necrosis factor-α pretreatment is protective in a rat model of myocardial ischemia-reperfusion injury. Biochem. Biophys Res. Comm. 184, 1056–1059 (1992).

    Article  CAS  PubMed  Google Scholar 

  63. Yamashita, N. et al. The involvement of cytokines in the second window of ischaemic preconditioning. Br. J. Pharmacol. 131, 415–422 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Nawashiro, H., Tasaki, K., Ruetzler, C.A. & Hallenbeck, J.M. TNF-α pretreatment induces protective effects against focal cerebral ischemia in mice. J. Cereb. Blood Flow Metab. 17, 483–490 (1997).

    Article  CAS  PubMed  Google Scholar 

  65. Cheng, B., Christakos, S. & Mattson, M.P. Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis. Neuron 12, 139–153 (1994).

    Article  CAS  PubMed  Google Scholar 

  66. Goodman, Y. & Mattson, M.P. Ceramide protects hippocampal neurons against excitotoxic and oxidative insults, and amyloid β-peptide toxicity. J. Neurochem. 66, 869–872 (1996).

    Article  CAS  PubMed  Google Scholar 

  67. Ginis, I. et al. TNF-α pretreatment prevents subsequent activation of cultured brain cells with TNF-α and hypoxia via ceramide. Am. J. Physiol. 276, C1171–1183 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Liu, J., Ginis, I., Spatz, M. & Hallenbeck, J.M. Hypoxic preconditioning protects cultured neurons against hypoxic stress via TNF-α and ceramide. Am. J. Physiol. Cell. Physiol. 278, C144–153 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Ginis, I. et al. TNF-α-induced tolerance to ischemic injury involves differential control of NF-κB transactivation: the role of NF-κB association with p300 adaptor. J. Cereb. Blood Flow Metab. 22, 142–152 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Ellison, J.A., Barone, F.C. & Feuerstein, G.Z. Matrix remodeling after stroke. De novo expression of matrix proteins and integrin receptors. Ann. NY Acad. Sci. 890, 204–222 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Rubin, E.M. & Tall, A. Perspectives for vascular genomics. Nature 407, 265–269 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Pandey, A. & Mann, M. Proteomics to study genes and genomes. Nature 405, 837–46 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Kitano, H. Systems biology: a brief overview. Science 295, 1662–1664 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Ghosh, S. & Karin, M. Missing pieces in the NF-κB puzzle. Cell 109 Suppl, S81–96 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Tang, G. et al. Inhibition of JNK activation through NF-κB target genes. Nature 414, 313–317 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. De Smaele, E. et al. Induction of gadd45β by NF-κB downregulates pro-apoptotic JNK signalling. Nature 414, 308–313 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Baeuerle, P.A. & Baltimore, D. Activation of DNA-binding activity in an apparently cytoplasmic precursor of the NF-κ B transcription factor. Cell 53, 211–217 (1988).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

I thank C. Ludlow for useful comments on the manuscript.

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  1. Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA

    John M. Hallenbeck

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Hallenbeck, J. The many faces of tumor necrosis factor in stroke. Nat Med 8, 1363–1368 (2002). https://doi.org/10.1038/nm1202-1363

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