Skip to main content
SpringerLink
Log in

Expression of TNF and TNF Receptors (p55 and p75) in the Rat Brain after Focal Cerebral Ischemia

  • Original Articles
  • Published:
Molecular Medicine Aims and scope Submit manuscript

Abstract

Cerebral ischemia induces a rapid and dramatic up-regulation of tumor necrosis factor (TNF) protein and mRNA, but the cellular sources of TNF in the ischemic brain have not been defined. The diverse activities of TNF are mediated via ligand interaction with two distinct receptors, p55 and p75, which activate separate intracellular signal transduction pathways, leading to distinct biological effects. Since the effects of cerebral ischemia on TNF receptor (TNFR) expression are unknown, we examined the cellular localization and protein expression of TNF and its two receptors in the rat cerebral cortex in response to permanent middle cerebral artery (MCA) occlusion. The results indicate that focal cerebral ischemia up-regulates expression of TNF and both TNFRs within the ischemic cortex. The most abundant type of TNF irrimunoreactivity (ER) was a punctate and filamentous pattern of transected cellular processes; however, cell bodies of neurons, astrocytes, and microglia, as well as infiltrating polymorphonuclear (PMN) leukocytes also showed TNF IR. Brain vasculature displayed TNF IR not only within endothelial cells but also in the perivascular space. MCA occlusion induced significant up-regulation of TNF receptors, with p55 IR appearing within 6 hr, significantly before the appearance of p75 IR at 24 hr after the onset of ischemia. Since p55 has been implicated in transducing cytotoxic signalling of TNF, these results support the proposed injurious role of excessive TNF produced during the acute response to cerebral ischemia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Buttini M, Appel K, Sauter A, Gebicke-Haerter P-J, Boddeke H. (1996) Expression of tumor necrosis factor alpha after focal cerebral ischemia in the rat. Neuroscience 71: 1–16.

    Article  CAS  PubMed  Google Scholar 

  2. Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC, Feuerstein GZ. (1994) Tumor necrosis factor-a expression in ischemic neurons. Stroke 25: 1481–1488.

    Article  CAS  PubMed  Google Scholar 

  3. Taupin V, Toulmond S, Serrano A, Benavides J, Zavala F. (1993) Increase in IL-6, IL-1 and TNF levels in rat brain following traumatic lesions. J. Neuroimmunol 42: 177–186.

    Article  CAS  PubMed  Google Scholar 

  4. Woodroofe MN, Sarna GS, Wadhwa M, et al. (1991) Detection of interleukin-1 and inter-leukin-6 in adult rat brain following mechanical injury, by in vivo microdialysis: Evidence of a role for microglia in cytokine production. J. Neuroimmunol 33: 227–236.

    Article  CAS  PubMed  Google Scholar 

  5. Tchelingerian J-L, Quinonero J, Booss J, Jacque C. (1993) Localization of TNF-α and IL-1 immunoreactivities in striatal neurons after surgical injury to hippocampus. Neuron. 10: 213–224.

    Article  CAS  PubMed  Google Scholar 

  6. Fan L, Young PR, Barone FC, Feuerstein GZ, Smith DH, Mcintosh TK. (1996) Experimental brain injury induces differential expression of tumor necrosis factor-mRNA in the CNS. Mol. Brain Res. 36: 287–291.

    Article  CAS  PubMed  Google Scholar 

  7. Szaflarski J, Burtrum D, Silverstein FS. (1995) Cerebral hypoxia-ischemia stimulates cytokine gene expression in perinatal rats. Stroke 26: 1093–1100.

    Article  CAS  PubMed  Google Scholar 

  8. Tracey KJ, Vlassara H, Cerami A. (1989) Ca-chectin/tumour necrosis factor. Lancet I: 1122–1126.

    Article  Google Scholar 

  9. Barone FC, Arvin B, White RF, Miller A, Webb CL, Willette RN, Lysko PG, Feuerstein GZ. (1997) Tumor necrosis factor-α. A mediator of focal ischemic brain injury. Stroke 28: 1233–1244.

    Article  CAS  PubMed  Google Scholar 

  10. Meistreil III ME, Botchkina Gl, Wang H, De-Santo E, Cockroft KM, Bloom O, Vishnub-hakat JM, Ghezzi P, Tracey KJ. (1997) TNF is a brain-damaging cytokine in cerebral ischemia. Shock In press.

  11. Dawson DA, Martin D, Hallenbeck JM. (1996) Inhibition of tumor necrosis factor-alpha reduces focal cerebral ischemic injury in the spontaneously hypertensive rat. Neu-rosci. Lett. 218: 41–44.

    Article  CAS  Google Scholar 

  12. Navashiro H, Martin D, Hallenbeck JM. (1997) Inhibition of tumor necrosis factor and amelioration of brain infarction in mice. J. Cereb. Blood Flow Metab. 17: 229–232.

    Article  Google Scholar 

  13. Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK, Holtsbert FW, Mattson MP. (1996) Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nature Med. 2: 788–794.

    Article  CAS  PubMed  Google Scholar 

  14. Aggarwal BB. (1992) Comparative analysis of the structure and function of TNF-α and TNF-β. Immunol. Ser. 56: 61–78.

    PubMed  CAS  Google Scholar 

  15. Turetskaya RL, Fashena SJ, Paul NL, Ruddle NH. (1992) Genomic structure, induction, and production of TNF-α. Immunol. Ser. 56: 35–60.

    PubMed  CAS  Google Scholar 

  16. Frei K, Siepl C, Groscurth P, Bodmer S, Schwerdel C, Fontana A. (1987) Antigen presentation and tumor cytotoxicity by interferon-γ-treated microglial cells. Eur. J. Immunol. 17: 1271–1278.

    Article  CAS  PubMed  Google Scholar 

  17. Sawada M, Kondo N, Suzumura A, Marunouchi T. (1989) Production of TNF-α by microglia and astrocytes in culture. Brain Res. 491: 394–397.

    Article  CAS  PubMed  Google Scholar 

  18. Lieberman AP, Pitha PM, Shin HS, Shin ML. (1989) Production of tumor necrosis factor and other cytokines by astrocytes stimulated with lipopolysaccharide or a neurotropic virus. Froc. Natl Acad. Sei. U.S.A. 86: 6348–6352.

    Article  CAS  Google Scholar 

  19. Chung IY, Benveniste EN. (1990) Tumor necrosis factor alpha production by astrocytes. Induction by lipopolysaccharide, interferon gamma and interleukin 1 beta. J. Immunol. 144: 2999–3007.

    PubMed  CAS  Google Scholar 

  20. Wesselingh SL, Gough NM, Finlay-Jones JJ, McDonald PJ. (1990) Detection of cytokine mRNA in astrocyte culture using the polymerase chain reaction. Lymphokine Res. 9: 177–185.

    PubMed  CAS  Google Scholar 

  21. Tarlow MJ, Jenkins R, Comist SD, Osborne MP, Stephens S, Stanley P, Crokers J. (1993) Ependymal cells of the choroid plexus express tumour necrosis factor-α. Neuropathol. Appl. Neurobiol. 19: 324–328.

    Article  CAS  PubMed  Google Scholar 

  22. Beutler B. (1992) Tumor Necrosis Factors: The Molecules and Their Emerging Role in Medicine. New York, Raven Press.

    Google Scholar 

  23. Tartaglia LA, Goeddel DV. (1992) Two TNF receptors. Immunol. Today 13: 151–153.

    Article  CAS  PubMed  Google Scholar 

  24. Rothe J, Gehr G, Loetscher H, Lesslauer W. (1992) Tumor necrosis factor receptors— structure and function. Immunol. Res. 11: 81–90.

    Article  CAS  PubMed  Google Scholar 

  25. Pfizenmaier K, Himmler A, Schutze S, Scheurich P, Kronke M. (1992) TNF receptors and TNF signal transduction. Beutler B (ed). In Tumor Necrosis Factors: The molecules and their emerging role in medicine. Raven Press, New York, pp. 439–472.

    Google Scholar 

  26. Vandenabeele P, Declercq W, Beyaert R, Fiers W (1995) Two tumor necrosis factor receptors: structure and function. Trends Cell Biol. 5: 392–399.

    Article  CAS  PubMed  Google Scholar 

  27. Smith CA, Farrah T, Goodwin RG. (1994) The TNF receptor superfamily of cellular and viral proteins: Activation, costimulation and death. Cell 76: 959–962.

    Article  CAS  PubMed  Google Scholar 

  28. Tartaglia LA, Weber RF, Figari IS, Reynolds C, Pallachino MA, Jr, Goeddell DV. (1991) The two different receptors for tumor necrosis factor mediate distinct cellular responses. Froc. Natl. Acad. Sei. U.S.A. 88: 9292–9295.

    Article  CAS  Google Scholar 

  29. Tartaglia LA, Goeddell DV, Reynolds C, Figari IS, Weber RF, Fendly BM, Palladino MA. (1993) Stimulation of human T-cell proliferation by specific activation of the 75-kD tumor necrosis factor receptor. J. Immunol. 151: 4637–4641.

    PubMed  CAS  Google Scholar 

  30. Grell M, Scheurich P, Meager A, Pfizenmaier K. (1993) TR60 and TR80 tumor necrosis factor (TNF)-receptors can independently mediate cytolysis. Lymphokine and Cytokine Res. 12, Nov. 3: 143–148.

    CAS  Google Scholar 

  31. Tada M, Diserens A-C, Desbaillets I, et al. (1994) Analysis of cytokine receptor messenger RNA expression in human glioblastoma cells and normal astrocytes by reverse transcription polymerase chain reaction. J. Neurosurs. 80: 1063–1073.

    Article  CAS  Google Scholar 

  32. Shen Y, Li R, Shiosaki K. (1997) Inhibition of p75 tumor necrosis factor receptor by antisense oligonucleotides increases hypoxic injury and beta-amyloid toxicity in a human neuronal cell line. J. Biol. Chem. 272: 3550–3553.

    Article  CAS  PubMed  Google Scholar 

  33. Zimmerman GA, Meistrell M IH, Bloom O, Cockroft KM, Bianchi M, Risucci D, Broom J, Farmer P, Cerami A, Vlassara H, et al. (1995) Neurotoxicity of advanced glycation endproducts (AGEs) during focal stroke, and neuroprotective effects of aminoguanidine. Froc. Natl. Acad. Sei. U.S.A. 92: 3744–3748.

    Article  CAS  Google Scholar 

  34. Cockroft KM, Meistrell M III, Zimmerman GA, Risucci D, Bloom O, Cerami A, Tracey KJ. (1996) Cerebroprotective effects of aminoguanidine in a rodent model of stroke. Stroke 27: 1393–1398.

    Article  CAS  PubMed  Google Scholar 

  35. Breder CD, Tsujimoto M, Terano Y, Scott DW, Saper CB. (1993) Distribution and car-acterization of tumor necrosis factor-α-like immunoreactivity in the murinecentral nervous system. J. Comp. Neurol. 337: 543–567.

    Article  CAS  PubMed  Google Scholar 

  36. Kato HK, Kogure T, Araki T, Itoyoma Y. (1994) Astroglial and microglial responses in the gerbil hippocampus with induced ischemic intolerance. Brain Res. 664: 69–76.

    Article  CAS  PubMed  Google Scholar 

  37. Korematsu K, Goto S, Nagahiro S, Ushio Y. (1994) Microglial response to transient focal ischemia: An immunocytochemical study on the rat cerebral cortex using anti-phospho-tyrosine antibody. J. Cereb. Blood Flow Metab. 14: 825–830.

    Article  CAS  PubMed  Google Scholar 

  38. Nishino H, Czurko A, Fukuda A, Hashitani T, Hida H, Karadi Z, Lenard L. (1994) Pathophysiological processes after transient ischemia of the middle cerebral artery in the rat. Brain Res. Bull. 35: 51–56.

    Article  CAS  PubMed  Google Scholar 

  39. Zimmer LA, Ennis M, Shipley MT. (1997) Soman-induced seizures rapidly activate astrocytes and microglia discrete brain regions. J. Comp. Neurol. 378: 482–492.

    Article  CAS  PubMed  Google Scholar 

  40. Garcia JE, Nonner D, Ross D, Barrett JN. (1992) Neurotoxic components in normal serum. Exp. Neurol. 118: 309–316.

    Article  CAS  PubMed  Google Scholar 

  41. Piani D, Spangler M, Schaffner A, Montana A. (1992) Macrophage-induced cytoxicity of N-methyl-D-aspartate receptor positive neurons involves excitatory amino acids rather than reactive oxygen intermediates and cytokines. Eur. J. Immunol. 22: 2429–2436.

    Article  CAS  PubMed  Google Scholar 

  42. Hahn T, Toker L, Budilovsky S, Aderka D, Eahhar Z, Wallach D. (1985) Use of monoclonal antibodies to a human cytotoxin for its isolation and for examining the self-induction of resistance to this protein. Proc. Natl. Acad. Sei. U.S.A. 82: 3814–3818.

    Article  CAS  Google Scholar 

  43. Nophar Y, Holtmann H, Ber R, Wallach D. (1988) Dominance of resistance to the cytocidal effect of tumor necrosis factor in heterokarions by fusion of resistant and sensitive cells. J. Immunol. 140: 3456–3460.

    PubMed  CAS  Google Scholar 

  44. Wallach D. (1997) Cell death induction by TNF: A matter of self control. Trends Biochem. Sei. 22: 107–109.

    Article  CAS  Google Scholar 

  45. Peck R, Brockhaus M, Frey JR. (1989) Cell surface tumor necrosis factor (TNF) accounts for monocyte- and lymphocyte-mediated killing of TNF-resistant target cells. Cell Immunol. 122: 1–10.

    Article  PubMed  Google Scholar 

  46. Macchia D, Almeriogna F, Parronchi P, Ravina A, Maggi E, Romagnani S. (1993) Membrane tumor necrosis factor is involved in the polyclonal B-cell activation induced by HIV infected human T-cells. Nature 363: 464–466.

    Article  CAS  PubMed  Google Scholar 

  47. Georgopulos S, Plows D, Kollias G. (1996) Transmembrane TNF is sufficient to induce localized tissue toxicity and chronic inflammatory arthritis in transgenic mice. J. Inflammation 46: 86–87.

    Google Scholar 

  48. Robbins DS, Shirazi Y, Drysdale B-E, Lieberman A, Shin HS, Shin ML. (1987) Production of cytotoxic factor from oligodentro-cytes by stimulated astrocytes. J. Immunol. 139: 2593–2597.

    PubMed  CAS  Google Scholar 

  49. Hofman FM, Hinton DR, Johnson K, Merill JE. (1989) Tumor necrosis factor identified in multiple sclerosis brain. J. Exp. Med. 170: 607–612.

    Article  CAS  PubMed  Google Scholar 

  50. Arvin B, Neville LF, Barone FC, Feuerstein GK. (1995) Brain injury and inflammation. A putative role of TNF alpha. Ann. N.Y. Acad. Sei. 765: 62–99.

    Article  CAS  Google Scholar 

  51. Wang XK, Yue T-L, Young PR, Barone FR, Feuerstein GZ. (1995) Expression of inter-leukin-6, c-fos, and zif268 mRNAs in rat ischemic cortex. J. Cereb. Blood Flow Metab. 15: 166–171.

    Article  CAS  PubMed  Google Scholar 

  52. Clark WM, Madden KP, Rothlein R, Zivin JA. (1991) Reduction of central nervous system ischemic injury by monoclonal antibody to intercellular adhesion molecule. J. Neuro-surg. 75: 623–627.

    CAS  Google Scholar 

  53. Bowles WP, Zivin JA, Rothlein R. (1993) Monoclonal antibody to the ICAM-1 adhesion site reduces neurological damage in a rabbit cerebral embolism stroke model. Exp. Neurol. 119: 215–219.

    Article  Google Scholar 

  54. Zhang RL, Chopp M, Li Y, Zaloga C, Jiang N, Jones M, Miyasaka M, Ward P. (1994) Anti-ICAM-1 antibody reduces ischemic cell damage after transcient middle cerebral artery occlusion in the rat. Neurology 44: 1747–1751.

    Article  CAS  PubMed  Google Scholar 

  55. Dubravec DB, Spriggs DR, Mannick JA, Rodrick ML. (1990) Circulating human peripheral blood granulocytes synthesize and secrete tumor necrosis factor alpha. Proc. Natl. Acad. Sei. U.S.A. 87: 6758–6761.

    Article  CAS  Google Scholar 

  56. Chen H, Chopp M, Bodzin G. (1992) Neuro-tropenia reduces the volume of cerebral infarct after transient middle cerebral occlusion in the rat. Neurosci. Res. Commun. 11: 93–99.

    Google Scholar 

  57. Shiga Y, Onnodera H, Kogere K, Yamasaki Y, Yashima Y, Syozuhara H, Sendo F. (1991) Neutrophil as a mediator of ischemic edema formation in the brain. Neurosci. Lett. 125: 110–112.

    Article  CAS  PubMed  Google Scholar 

  58. Sippy BD, Hofman FM, Wallach D, Hinton DR. (1995) Increased expression of tumor necrosis factor-receptors in the brain of patients with AIDS. J. AIDS Hum. Retrovirol. 10: 511–521.

    CAS  Google Scholar 

  59. Van Zee KJ, Kohno T, Fischer E, Rock CS, Moldawer LL, Lowry SF. (1992) Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo. Proc. Natl. Acad. Sei. U.S.A. 89: 4845–4849.

    Article  Google Scholar 

  60. Keel M, Bonaccio M, Steckholder U, Ungethum U, Gallati H, Trentz O, Ertel W. (1995) Increased plasma level of Type 1 (p55) TNF-receptors following trauma. Swiss Surg. 5: 241–244.

    Google Scholar 

  61. Pinckard JK, Sheehan KC, Arthur CD, Schreiber. (1997) Constitutive shedding of both p55 and p75 murine TNF receptors in vivo. J. Immunol. 158: 3869–3873.

    PubMed  CAS  Google Scholar 

  62. Banner D, D’Arcy A, Janes W, Gentz R, Schoenfeld H-J, Broger C, Loetscher H, Lesslauer W. (1993) Crystal structure of the soluble human 5 5 kd TNF receptor-human TNF-complex: Implications for TNF receptor activation. Cell 73: 431–445.

    Article  CAS  PubMed  Google Scholar 

  63. Chao CC, Hu S. (1994) Tumor necrosis factor-alpha potentiates glutamate neurotoxicity in human fetal brain cell cultures. Dev. Neurosci. 16: 172–179.

    Article  CAS  PubMed  Google Scholar 

  64. Cheng B, Christakos S, Mattson MP. (1994) Tumor necrosis factors protect neurons against excitotoxic metabolic insults and promote maintenance of calcium homeostasis. Neuron 12: 139–153.

    Article  CAS  PubMed  Google Scholar 

  65. Shohami E, Bass R, Wallach D, Yamin A, Gallily R. (1996) Inhibition of tumor necrosis factor alpha activity in rat brain is associated with cerebroprotection after closed head injury. J. Cereb. Blood Flow Metab. 16: 378–384.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Picower Institute for Medical Research, 350 Community Drive, Manhasset, New York, 11030, USA

    Galina I. Botchkina, Malcolm E. Meistrell III, Inna L. Botchkina & Kevin J. Tracey

  2. Department of Surgery, North Shore University Hospital, Manhasset, New York, USA

    Kevin J. Tracey

Authors
  1. Galina I. Botchkina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Malcolm E. Meistrell III
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Inna L. Botchkina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kevin J. Tracey
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Botchkina, G.I., Meistrell, M.E., Botchkina, I.L. et al. Expression of TNF and TNF Receptors (p55 and p75) in the Rat Brain after Focal Cerebral Ischemia. Mol Med 3, 765–781 (1997). https://doi.org/10.1007/BF03401714

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03401714

Keywords

Search

Navigation