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The duality of the inflammatory response to traumatic brain injury

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Abstract

One and a half to two million people sustain a traumatic brain injury (TBI) in the US each year, of which approx 70,000–90,000 will suffer from long-term disability with dramatic impacts on their own and their families’ lives and enormous socio-economic costs. Brain damage following traumatic injury is a result of direct (immediate mechanical disruption of brain tissue, or primary injury) and indirect (secondary or delayed) mechanisms. These secondary mechanisms involve the initiation of an acute inflammatory response, including breakdown of the blood-brain barrier (BBB), edema formation and swelling, infiltration of peripheral blood cells and activation of resident immunocompetent cells, as well as the intrathecal release of numerous immune mediators such as interleukins and chemotactic factors. An overview over the inflammatory response to trauma as observed in clinical and in experimental TBI is presented in this review. The possibly harmful/beneficial sequelae of post-traumatic inflammation in the central nervous system (CNS) are discussed using three model mediators of inflammation in the brain, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and transforming growth factor-β (TGF-β). While the former two may act as important mediators for the initiation and the support of post-traumatic inflammation, thus causing additional cell death and neurologic dysfunction, they may also pave the way for reparative processes. TGF-β, on the other hand, is a potent anti-inflammatory agent, which may also have some deleterious long-term effects in the injured brain. The implications of this duality of the post-traumatic inflammatory response for the treatment of brain-injured patients using anti-inflammatory strategies are discussed.

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References

  1. Marmarou A., Anderson R. L., Ward J. D., Choi S. C., Young H. F., Eisenberg H. M., et al. (1991) Impact of ICP instability and hypotension on outcome in patients with severe head trauma. J. Neurosurg. 75, S59-S66.

    Google Scholar 

  2. Unterberg A. W., Stroop R., Thomale U. W., Kiening K. L., Pauser S., and Vollmann W. (1997) Characterisation of brain edema following "controlled cortical impact injury" in rats. Acta Neurochir. (Supp.) 70, 106–108.

    CAS  Google Scholar 

  3. Baskaya M. K., Rao A. M., Dogan A., Donaldson D., and Dempsey R. J. (1997) The biphasic opening of the blood-brain barrier in the cortex and hippocampus after traumatic brain injury in rats. Neurosci. Lett. 226, 33–36.

    PubMed  CAS  Google Scholar 

  4. Hicks R. R., Baldwin S. A., and Scheff S. W. (1997) Serum extravasation and cytoskeletal alterations following traumatic brain injury in rats. Comparison of lateral fluid percussion and cortical impact models. Mol. Chem. Neuropathol. 32, 1–16.

    PubMed  CAS  Google Scholar 

  5. Barzo P., Marmarou A., Fatouros P., Corwin F., and Dunbar J. (1996) Magnetic resonance imaging-monitored acute blood-brain barrier changes in experimental traumatic brain injury. J. Neurosurg. 85, 1113–1121.

    PubMed  CAS  Google Scholar 

  6. Fukuda K., Tanno H., Okimura Y., Nakamura M., and Yamaura A. (1995) The blood-brain barrier disruption to circulating proteins in the early period after fluid percussion brain injury in rats. J. Neurotrauma 12, 315–324.

    PubMed  CAS  Google Scholar 

  7. Soares H. D., Thomas M., Cloherty K., and McIntosh T. K. (1992) Development of prolonged focal cerebral edema and regional cation changes following experimental brain injury in the rat. J. Neurochem. 58, 1845–1852.

    PubMed  CAS  Google Scholar 

  8. Cortez S. C., McIntosh T. K., and Noble L. J. (1989) Experimental fluid percussion brain injury: vascular disruption and neuronal and glial alterations. Brain Res. 482, 271–282.

    PubMed  CAS  Google Scholar 

  9. Csuka E., Morganti-Kossmann M. C., Lenzlinger P. M., Joller H., Trentz O., and Kossmann T. (1999) IL-10 levels in cerebrospinal fluid and serum of patients with severe traumatic brain injury: relationship to IL-6, TNF-alpha, TGF-beta1 and blood-brain barrier function. J. Neuroimmunol. 101, 211–221.

    PubMed  CAS  Google Scholar 

  10. Morganti-Kossmann M. C., Hans V. H., Lenzlinger P. M., Dubs R., Ludwig E., Trentz O., and Kossmann T. (1999) TGF-beta is elevated in the CSF of patients with severe traumatic brain injuries and parallels blood-brain barrier function. J. Neurotrauma 16, 617–628.

    PubMed  CAS  Google Scholar 

  11. Pleines U. E., Stover J. F., Kossmann T., Trentz O., and Morganti-Kossmann M. C. (1998) Soluble ICAM-1 in CSF coincides with the extent of cerebral damage in patients with severe traumatic brain injury. J. Neurotrauma 15, 399–409.

    PubMed  CAS  Google Scholar 

  12. Soares H. D., Hicks R. R., Smith D., and McIntosh T. K. (1995) Inflammatory leukocytic recruitment and diffuse neuronal degeneration are separate pathological processes resulting from traumatic brain injury. J. Neurosci. 15, 8223–8233.

    PubMed  CAS  Google Scholar 

  13. Stahel P. F., Shohami E., Younis F. M., Kariya K., Otto V. I., Lenzlinger P. M., et al. (2000) Experimental closed head injury: analysis of neurological outcome, blood-brain barrier dysfunction, intracranial neutrophil infiltration, and neuronal cell death in mice deficient in genes for pro-inflammatory cytokines. J. Cereb. Blood Flow Metab. 20, 369–380.

    PubMed  CAS  Google Scholar 

  14. Zhuang J., Shackford S. R., Schmoker J. D., and Anderson M. L. (1993) The association of leukocytes with secondary brain injury. J. Trauma 35, 415–422.

    PubMed  CAS  Google Scholar 

  15. Carlos T. M., Clark R. S., Franicola-Higgins D., Schiding J. K., and Kochanek P. M. (1997) Expression of endothelial adhesion molecules and recruitment of neutrophils after traumatic brain injury in rats. J. Leukocyte Biol. 61, 279–285.

    PubMed  CAS  Google Scholar 

  16. Isaksson J., Lewen A., Hillered L., and Olsson Y. (1997) Up-regulation of intercellular adhesion molecule 1 in cerebral microvessels after cortical contusion trauma in a rat model. Acta Neuropathol. 94, 16–20.

    PubMed  CAS  Google Scholar 

  17. Shibayama M., Kuchiwaki H., Inao S., Yoshida K., and Ito M. (1996) Intercellular adhesion molecule-1 expression on glia following brain injury: participation of interleukin-1 beta. J. Neurotrauma 13, 801–808.

    PubMed  CAS  Google Scholar 

  18. Rancan M., Otto V. I., Hans V. H., Gerlach I., Jork R., Trentz O., et al. (2001) Upregulation of ICAM-1 and MCP-1 but not of MIP-2 and sensorimotor deficit in response to traumatic axonal injury in rats. J. Neurosci. Res. 63, 438–446.

    PubMed  CAS  Google Scholar 

  19. Quattrocchi K. B., Miller C. H., Wagner F. C., Jr., DeNardo S. J., DeNardo G. L., Ovodov K., and Frank E. H. (1992) Cell-mediated immunity in severely head-injured patients: the role of suppressor lymphocytes and serum factors. J. Neurosurg. 77, 694–699.

    PubMed  CAS  Google Scholar 

  20. Quattrocchi K. B., Issel B. W., Miller C. H., Frank E. H., and Wagner F. C., Jr. (1992) Impairment of helper T-cell function following severe head injury. J. Neurotrauma 9, 1–9.

    PubMed  CAS  Google Scholar 

  21. Quattrocchi K. B., Frank E. H., Miller C. H., MacDermott J. P., Hein L., Frey L., and Wagner F. C., Jr. (1990) Suppression of cellular immune activity following severe head injury. J. Neurotrauma 7, 77–87.

    PubMed  CAS  Google Scholar 

  22. Hoyt D. B., Ozkan A. N., Hansbrough J. F., Marshall L., and vanBerkum-Clark M. (1990) Head injury: an immunologic deficit in T-cell activation. J. Trauma 30, 759–766.

    PubMed  CAS  Google Scholar 

  23. Piek J., Chesnut R. M., Marshall L. F., Berkum-Clark M., Klauber M. R., Blunt B. A., et al. (1992) Extracranial complications of severe head injury. J. Neurosurg. 77, 901–907.

    PubMed  CAS  Google Scholar 

  24. Perry V. H., Anthony D. C., Bolton S. J., and Brown H. C. (1997) The blood-brain barrier and the inflammatory response. Mol. Med. Today 3, 335–341.

    PubMed  CAS  Google Scholar 

  25. Holmin S., Soderlund J., Biberfeld P., and Mathiesen T. (1998) Intracerebral inflammation after human brain contusion. Neurosurgery 42, 291–298.

    PubMed  CAS  Google Scholar 

  26. Holmin S., Mathiesen T., Shetye J., and Biberfeld P. (1995) Intracerebral inflammatory response to experimental brain contusion. Acta. Neurochir. 132, 110–119.

    CAS  Google Scholar 

  27. Lenzlinger P. M., Hans V. H. J., Morganti-Kossmann M. C., Joller H., Trentz O., and Kossmann T. (2001) Markers for cell-mediated immune response are elevated in cerebrospinal fluid and serum after severe traumatic brain injury in humans. J. Neurotrauma 18, 479–489.

    PubMed  CAS  Google Scholar 

  28. Aihara N., Hall J. J., Pitts L. H., Fukuda K., and Noble L. J. (1995) Altered immunoexpression of microglia and macrophages after mild head injury. J. Neurotrauma 12, 53–63.

    PubMed  CAS  Google Scholar 

  29. Korematsu K., Goto S., Nagahiro S., and Ushio Y. (1994) Microglial response to transient focal cerebral ischemia: an immunocytochemical study on the rat cerebral cortex using antiphosphotyrosine antibody. J. Cereb. Blood Flow Metab. 14, 825–830.

    PubMed  CAS  Google Scholar 

  30. Kreutzberg G. W. (1996) Microglia: a sensor for pathological events in the CNS. TINS 19, 312–318.

    PubMed  CAS  Google Scholar 

  31. Popovich P. G., Wei P., and Stokes B. T. (1997) Cellular inflammatory response after spinal cord injury in Sprague- Dawley and Lewis rats. J. Comp. Neurol. 377, 443–464.

    PubMed  CAS  Google Scholar 

  32. Spranger M. and Fontana A. (1996) Activation of microglia: a dangerous interlude in immune function in the brain. Neuroscientist 2, 293–299.

    Google Scholar 

  33. Thomas W. E. (1992) Brain macrophages: evaluation of microglia and their functions. Brain Res. Rev. 17, 61–74.

    PubMed  CAS  Google Scholar 

  34. Yamashita K., Niwa M., Kataoka Y., Shigematsu K., Himeno A., Tsutsumi K., et al. (1994) Microglia with an endothelin ETB receptor aggregate in rat hippocampus CA1 subfields following transient forebrain ischemia. J. Neurochem. 63, 1042–1051.

    PubMed  CAS  Google Scholar 

  35. Morganti-Kossmann M. C., Lenzlinger P. M., Hans V., Stahel P., Csuka E., Ammann E., et al. (1997) Production of cytokines following brain injury: beneficial and deleterious for the damaged tissue. Mol. Psychiatry 2, 133–136.

    Google Scholar 

  36. Ott L., McClain C. J., Gillespie M., and Young B. (1994) Cytokines and metabolic dysfunction after severe head injury. J. Neurotrauma 11, 447–472.

    PubMed  CAS  Google Scholar 

  37. Hans V. H., Kossmann T., Joller H., Otto V., and Morganti-Kossmann M. C. (1999) Interleukin-6 and its soluble receptor in serum and cerebrospinal fluid after cerebral trauma. Neuroreport 10, 409–412.

    PubMed  CAS  Google Scholar 

  38. Rothwell N. J. and Hopkins S. J. (1995) Cytokines and the nervous system II: Actions and mechanisms of action. TINS 18, 130–136.

    PubMed  CAS  Google Scholar 

  39. Bell M. J., Kochanek P. M., Doughty L. A., Carcillo J. A., Adelson P. D., Clark R. S., et al. (1997) Interleukin-6 and interleukin-10 in cerebrospinal fluid after severe traumatic brain injury in children. J. Neurotrauma 14, 451–457.

    PubMed  CAS  Google Scholar 

  40. Kossmann T., Hans V. H., Imhof H. G., Stocker R., Grob P., Trentz O., and Morganti-Kossmann C. (1995) Intrathecal and serum interleukin-6 and the acute-phase response in patients with severe traumatic brain injuries. Shock 4, 311–317.

    PubMed  CAS  Google Scholar 

  41. Kossmann T., Stahel P. F., Lenzlinger P. M., Redl H., Dubs R. W., Trentz O., Schlalg G., and Morganti-Kossmann M. C. (1997) Interleukin-8 released into the cerebrospinal fluid after brain injury is associated with blood-brain barier dysfunction and nerve growth factor production. J. Cereb. Blood Flow Metab. 17, 280–289.

    PubMed  CAS  Google Scholar 

  42. Goodman J. C., Robertson C. S., Grossman R. G., and Narayan R. K. (1990) Elevation of tumor necrosis factor in head injury. J. Neuroimmunol. 30, 213–217.

    PubMed  CAS  Google Scholar 

  43. Young A. B., Ott L. G., Beard D., Dempsey R. J., Tibbs P. A., and McClain C. J. (1988) The acute-phase response of the brain-injured patient. J. Neurosurg. 69, 375–380.

    PubMed  CAS  Google Scholar 

  44. Cohen D., Phillips R., Ott L., and Young B. (1991) Increased plasma and ventricular fluid interleukin-6 levels in patients with head injury. J. Lab. Clin. Med. 118, 225–231.

    PubMed  Google Scholar 

  45. McClain C. J., Cohen D., Ott L., Dinarello C. A., and Young B. (1987) Ventricular fluid interleukin-1 activity in patients with head injury. J. Lab. Clin. Med. 110, 48–54.

    PubMed  CAS  Google Scholar 

  46. Whalen M. J., Carlos T. M., Kochanek P. M., Wisniewski S. R., Bell M. J., Clark R. S., et al. (2000) Interleukin-8 is increased in cerebrospinal fluid of children with severe head injury. Crit. Care Med. 28, 929–934.

    PubMed  CAS  Google Scholar 

  47. Fan L., Young P. R., Barone F. C., Feuerstein G. Z., Smith D. H., and McIntosh T. K. (1995) Experimental brain injury induces expression of interleukin-1 beta mRNA in the rat brain. Mol. Brain Res. 30, 125–130.

    PubMed  CAS  Google Scholar 

  48. Fan L., Young P. R., Barone F. C., Feuerstein G. Z., Smith D. H., and McIntosh T. K. (1996) Experimental brain injury induces differential expression of tumor necrosis factor-alpha mRNA in the CNS. Mol. Brain Res. 36, 287–291.

    PubMed  CAS  Google Scholar 

  49. Knoblach S. M., Fan L., and Faden A. I. (1999) Early neuronal expression of tumor necrosis factor-alpha after experimental brain injury contributes to neurological impairment. J. Neuroimmunol. 95, 115–125.

    PubMed  CAS  Google Scholar 

  50. Shohami E., Novikov M., Bass R., Yamin A., and Gallily R. (1994) Closed head injury triggers early production of TNF alpha and IL-6 by brain tissue. J. Cereb. Blood Flow Metab. 14, 615–619.

    PubMed  CAS  Google Scholar 

  51. Woodroofe M. N., Sarna G. S., Wadhwa M., Hayes G. M., Loughlin A. J., Tinker A., and Cuzner M. L. (1991) Detection of interleukin-1 and interleukin-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.

    PubMed  CAS  Google Scholar 

  52. Taupin V., Toulmond S., Serrano A., Benavides J., and Zavala F. (1993) Increase in IL-6, IL-1 and TNF levels in rat brain following traumatic lesion. Influence of pre- and post-traumatic treatment with Ro5 4864, a peripheral-type (p site) benzodiazepine ligand. J. Neuroimmunol. 42, 177–185.

    PubMed  CAS  Google Scholar 

  53. Hans V. H., Kossmann T., Lenzlinger P. M., Probstmeier R., Imhof H. G., Trentz O., and Morganti-Kossmann M. C. (1999) Experimental axonal injury triggers interleukin-6 mRNA, protein synthesis and release into cerebrospinal fluid. J. Cereb. Blood Flow Metab. 19, 184–194.

    PubMed  CAS  Google Scholar 

  54. Benveniste E. N., Tang L. P., and Law R. M. (1995) Differential regulation of astrocyte TNF-alpha expression by the cytokines TGF-beta, IL-6 and IL-10. Int. J. Dev. Neurosci. 13, 341–349.

    PubMed  CAS  Google Scholar 

  55. Kolesnick R. and Golde D. W. (1994) The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signaling. Cell 77, 325–328.

    PubMed  CAS  Google Scholar 

  56. Sullivan P. G., Bruce-Keller A. J., Rabchevsky A. G., Christakos S., Clair D. K., Mattson M. P., and Scheff S. W. (1999) Exacerbation of damage and altered NF-kappaB activation in mice lacking tumor necrosis factor receptors after traumatic brain injury. J. Neurosci. 19, 6248–6256.

    PubMed  CAS  Google Scholar 

  57. Ross S. A., Halliday M. I., Campbell G. C., Byrnes D. P., and Rowlands B. J. (1994) The presence of tumor necrosis factor in CSF and plasma after severe head injury. Br. J. Neurosurg. 8, 419–425.

    PubMed  CAS  Google Scholar 

  58. Stover J. F., Schoning B., Beyer T. F., Woiciechowsky C., and Unterberg A. W. (2000) Temporal profile of cerebrospinal fluid glutamate, interleukin-6, and tumor necrosis factor-alpha in relation to brain edema and contusion following controlled cortical impact injury in rats. Neurosci. Lett. 288, 25–28.

    PubMed  CAS  Google Scholar 

  59. Rostworowski M., Balasingam V., Chabot S., Owens T., and Yong V. W. (1997) Astrogliosis in the neonatal and adult murine brain posttrauma: elevation of inflammatory cytokines and the lack of requirement for endogenous interferon-gamma. J. Neurosci. 17, 3664–3674.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  61. Stahel P. F., Kariya K., Shohami E., Barnum S. R., Eugster H., Trentz O., et al. (2000) Intracerebral complement C5a receptor (CD88) expression is regulated by TNF and lymphotoxin-alpha following closed head injury in mice. J. Neuroimmunol. 109, 164–172.

    PubMed  CAS  Google Scholar 

  62. Reid T. R., Torti F. M., and Ringold G. M. (1989) Evidence for two mechanisms by which tumor necrosis factor kills cells. J. Biol. Chem. 264, 4583–4589.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  64. Knoblach S. M. and Faden A. I. (1998) Interleukin-10 improves outcome and alters proin-flammatory cytokine expression after experimental traumatic brain injury. Exp. Neurol. 153, 143–151.

    PubMed  CAS  Google Scholar 

  65. Scherbel U., Raghupathi R., Nakamura M., Saatman K. E., Trojanowski J. Q., Neugebauer E., et al. (1999) Differential acute and chronic responses of tumor necrosis factor-deficient mice to experimental brain injury. Proc. Natl. Acad. Sci. USA 96, 8721–8726.

    PubMed  CAS  Google Scholar 

  66. Gadient R. A., Cron K. C., and Oten U. (1990) Interleukin-1 beta and tumor necrosis factor-alpha synergistically stimulate nerve growth factor (NGF) release from cultured rat astrocytes. Neurosci. Lett. 117, 335–340.

    PubMed  CAS  Google Scholar 

  67. Wu J., Kuo J., Liu Y., and Tzeng S. (2000) Tumor necrosis factor-alpha modulates the proliferation of neural progenitors in the subventricular/ventricular zone of adult rat brain. Neurosci. Lett. 292, 203–206.

    PubMed  CAS  Google Scholar 

  68. Mattson M. P. and Camandola S. (2001) NF-kappaB in neuronal plasticity and neurodegenerative disorders. J. Clin. Invest 107, 247–254.

    PubMed  CAS  Google Scholar 

  69. Nonaka M., Chen X. H., Pierce J. E., Leoni M. J., McIntosh T. K., Wolf J. A., and Smith D. H. (1999) Prolonged activation of NF-kappaB following traumatic brain injury in rats. J. Neurotrauma 16, 1023–1034.

    PubMed  CAS  Google Scholar 

  70. Gruol D. L. and Nelson T. E. (1997) Physiological and pathological roles of interleukin-6 in the central nervous system. Mol. Neurobiol. 15, 307–339.

    PubMed  CAS  Google Scholar 

  71. Vanden Berghe W., Vermeulen L., De Wilde G., De Bosscher K., Boone E., and Haegegeman G. (2000) Signal transduction by tumor necrosis factor and gene regulation of the inflammatory cytokine interleukin-6. Biochem. Pharmacol. 60, 1185–1195.

    Google Scholar 

  72. Kushima Y., Hama T., and Hatanaka H. (1992) Interleukin-6 as a neurotrophic factor for promoting the survival of cultured catecholaminergic neurons in a chemically defined medium from fetal and postnatal rat midbrains. Neurosci. Res. 13, 267–280.

    PubMed  CAS  Google Scholar 

  73. Marz P., Heese K., Dimitriades-Schmutz B., Rose-John S., and Otten U. (1999) Role of interleukin-6 and soluble IL-6 receptor in region-specific induction of astrocytic differentiation and neurotrophin expression. GLIA 26, 191–200.

    PubMed  CAS  Google Scholar 

  74. Frei K., Malipiero U. V., Leist T. P., Zinkernagel R. M., Schwab M. E., and Fontana A. (1989) On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases. Eur. J. Immunol. 19, 689–694.

    PubMed  CAS  Google Scholar 

  75. Benveniste E. N. (1998) Cytokine actions in the central nervous system. Cytokine Growth Factor Rev. 9, 259–275.

    PubMed  CAS  Google Scholar 

  76. Toulmond S., Vige X., Fage D., and Benavides J. (1992) Local infusion of interleukin-6 attenuates the neurotoxic effects of NMDA on rat striatal cholinergic neurons. Neurosci. Lett. 144, 49–52.

    PubMed  CAS  Google Scholar 

  77. Qiu Z., Sweeney D. D., Netzeband J. G., and Gruol D. L. (1998) Chronic interleukin-6 alters NMDA receptor-mediated membrane responses and enhances neurotoxicity in developing CNS neurons. J. Neurosci. 18, 10,445–10,456.

    CAS  Google Scholar 

  78. Kossmann T., Hans V., Imhof H. G., Trentz O., and Morganti-Kossmann M. C. (1996) Interleukin-6 released in human cerebrospinal fluid following traumatic brain injury may trigger nerve growth factor production in astrocytes. Brain Res. 713, 143–152.

    PubMed  CAS  Google Scholar 

  79. Campbell I. L., Abraham C. R., Masliah E., Kemper P., Inglis J. D., Oldstone M. B., and Mucke L. (1993) Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc. Natl. Acad. Sci. USA 90, 10061–10065.

    PubMed  CAS  Google Scholar 

  80. Fattori E., Lazzaro D., Musiani P., Modesti A., Alonzi T., and Ciliberto G. (1995) IL-6 expression in neurons of transgenic mice causes reactive astrocytosis and increase in ramified microglial cells but no neuronal damage. Eur. J. Neurosci. 7, 2441–2449.

    PubMed  CAS  Google Scholar 

  81. Penkowa M., Moos T., Carrasco J., Handberg H., Molinero A., Bluethmann H., and Hidalgo J. (1999) Strongly compromised inflammatory response to brain injury in interleukin-6-deficient mice. GLIA 25, 343–357.

    PubMed  CAS  Google Scholar 

  82. Laurer H. L., Lenzlinger P. M., and McIntosh T. K. (2000) Models of traumatic brain injury. Euro. J. Trauma 26, 95–100.

    Google Scholar 

  83. Rimaniol A. C., Lekieffre D., Serrano A., Masson A., Benavides J., and Zavala F. (1995) Biphasic transforming growth factor-beta production flanking the pro-inflammatory cytokine response in cerebral trauma. Neuroreport 7, 133–136.

    PubMed  CAS  Google Scholar 

  84. Chao C. C., Hu S., Sheng W. S., Tsang M., and Peterson P. K. (1995) Tumor necrosis factor-alpha mediates the release of bioactive transforming growth factor-beta in murine microglial cell cultures. Clin. Immunol. Immunopathol. 77, 358–365.

    PubMed  CAS  Google Scholar 

  85. da Cunha A. and Vitkovic L. (1992) Transforming growth factor-beta 1 (TGF-beta 1) expression and regulation in rat cortical astrocytes. J. Neuroimmunol. 36, 157–169.

    PubMed  Google Scholar 

  86. Zhou D., Munster A., and Winchurch R. A. (1991) Pathologic concentrations of interleukin 6 inhibit T cell responses via induction of activation of TGF-beta. FASEB J. 5, 2582–2585.

    PubMed  CAS  Google Scholar 

  87. Wahl S. M. (1994) Transforming growth factor beta: the good, the bad, and the ugly. J. Exp. Med. 180, 1587–1590.

    PubMed  CAS  Google Scholar 

  88. Finch C. E., Laping N. J., Morgan T. E., Nichols N. R., and Pasinetti G. M. (1993) TGF-beta 1 is an organizer of responses to neurodegeneration. J. Cell. Biochem. 53, 314–322.

    PubMed  CAS  Google Scholar 

  89. Zhu Y., Roth-Eichhorn S., Braun N., Culmsee C., Rami A., and Krieglstein J. (2000) The beta 1 (TGF-beta1) in hippocampal neurons: a temporary upregulated protein level after transient forebrain ischemia in the rat. Brain Res. 866, 286–298.

    PubMed  CAS  Google Scholar 

  90. Lehrmann E., Kiefer R., Christensen T., Toyka K. V., Zimmer J., Diemer N. H., et al. (1998) Microglia and macrophages are major sources of locally produced transforming growth factor-beta1 after transient middle cerebral artery occlusion in rats. GLIA 24, 437–448.

    PubMed  CAS  Google Scholar 

  91. Frei K., Piani D., Pfister H. W., and Fontana A. (1993) Immune-mediated injury in bacterial meningitis. Int. Rev. Exp. Pathol. 34 Pt B, 183–192.

    PubMed  Google Scholar 

  92. Ruocco A., Nicole O., Docagne F., Ali C., Chazalviel L., Komesli S., et al. (1999) A transforming growth factor-beta antagonist unmasks the neuroprotective role of this endogenous cytokine in excitotoxic and ischemic brain injury. J. Cereb. Blood Flow Metab. 19, 1345–1353.

    PubMed  CAS  Google Scholar 

  93. Henrich-Noack P., Prehn J. H., and Krieglstein J. (1994) Neuroprotective effects of TGF-beta 1. J. Neural Transm. Suppl 43, 33–45.

    PubMed  CAS  Google Scholar 

  94. Logan A. and Berry M. (1993) Transforming growth factor-beta 1 and basic fibroblast growth factor in the injured CNS. Trends Pharmacol. Sci. 14, 337–342.

    PubMed  CAS  Google Scholar 

  95. Logan A., Berry M., Gonzalez A. M., Frautschy S. A., Sporn M. B., and Baird A. (1994) Effects of transforming growth factor beta 1 on scar production in the injured central nervous system of the rat. Eur. J. Neurosci. 6, 355–363.

    PubMed  CAS  Google Scholar 

  96. Gray C. W. and Patel A. J. (1993) Regulation of beta-amyloid precursor protein isoform mRNAs by transforming growth factor-beta 1 and interleukin-1 beta in astrocytes. Brain Res. Mol. Brain. Res. 19, 251–256.

    PubMed  CAS  Google Scholar 

  97. Frautschy S. A., Yang F., Calderon L., and Cole G. M. (1996) Rodent models of Alzheimer’s disease: rat A beta infusion approaches to amyloid deposits. Neurobiol. Aging 17, 311–321.

    PubMed  CAS  Google Scholar 

  98. Mayeux R., Ottman R., Tang M. X., Noboa-Bauza L., Marder K., Gurland B., and Stern Y. (1993) Genetic susceptibility and head injury as risk factors for Alzheimer’s disease among community-dwelling elderly persons and their first-degree relatives. Ann. Neurol. 33, 494–501.

    PubMed  CAS  Google Scholar 

  99. Mortimer J. A., Van Duijn C. M., Chandra V., Fratiglioni L., Graves A. B., Heyman A., et al. (1991) Head trauma as a risk factor for Alzheimer’s disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group. Int. J. Epidemiol. 20(Suppl. 2), S28-S35.

    PubMed  Google Scholar 

  100. Roberts G. W., Gentleman S. M., Lynch A., Murray L., Landon M., and Graham D. I. (1994) Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer’s disease. J. Neurol. Neurosur. Psychiatry 57, 419–425.

    CAS  Google Scholar 

  101. Graham D. I., Gentleman S. M., Nicoll J. A., Royston M. C., McKenzie J. E., Roberts G. W., and Griffin W. S. (1996) Altered beta-APP metabolism after head injury and its relationship to the aetiology of Alzheimer’s disease. Acta. Neurochir. (Suppl.) 66, 96–102.

    CAS  Google Scholar 

  102. Lewen A., Li G. L., Nilsson P., Olsson Y., and Hillered L. (1995) Traumatic brain injury in rat produces changes of beta-amyloid precursor protein immunoreactivity. Neuroreport 6, 357–360.

    PubMed  CAS  Google Scholar 

  103. Pierce J. E., Trojanowski J. Q., Graham D. I., Smith D. H., and McIntosh T. K. (1996) Immunohistochemical characterization of alterations in the distribution of amyloid precursor proteins and beta-amyloid peptide after experimental brain injury in the rat. J. Neurosci. 16, 1083–1090.

    PubMed  CAS  Google Scholar 

  104. Van den Heuvel C., Blumbergs P. C., Finnie J. W., Manavis J., Jones N. R., Reilly P. L., and Pereira R. A. (1999) Upregulation of amyloid precursor protein messenger RNA in response to traumatic brain injury: an ovine head impact model. Exp. Neurol. 159, 441–450.

    PubMed  Google Scholar 

  105. Raby C. A., Morganti-Kossmann M. C., Kossmann T., Stahel P. F., Watson M. D., Evans L. M., et al. (1998) Traumatic brain injury increases beta-amyloid peptide 1–42 in cerebrospinal fluid. J. Neurochem. 71, 2505–2509.

    PubMed  CAS  Google Scholar 

  106. Emmerling M. R., Morganti-Kossmann M. C., Kossmann T., Stahel P. F., Watson M. D., Mehta P. D., et al. (2000) Traumatic brain injury elevates the Alzheimer’s amyloid peptide A beta 42 in human CSF. A possible role for nerve cell injury. Ann. NY Acad. Sci. 903, 118–122.

    PubMed  CAS  Google Scholar 

  107. Smith D. H., Nakamura M., McIntosh T. K., Wang J., Rodriguez A., Chen X. H., et al. (1998) Brain trauma induces massive hippocampal neuron death linked to a surge in beta-amyloid levels in mice overexpressing mutant amyloid precursor protein. Am. J. Pathol. 153, 1005–1010.

    PubMed  CAS  Google Scholar 

  108. Griffin W. S., Sheng J. G., Gentleman S. M., Graham D. I., Mrak R. E., and Roberts G. W. (1994) Microglial interleukin-1 alpha expression in human head injury: correlations with neuronal and neuritic beta-amyloid precursor protein expression. Neurosci. Lett. 176, 133–136.

    PubMed  CAS  Google Scholar 

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Correspondence to Tracy K. McIntosh.

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Lenzlinger, P.M., Morganti-Kossmann, MC., Laurer, H.L. et al. The duality of the inflammatory response to traumatic brain injury. Mol Neurobiol 24, 169–181 (2001). https://doi.org/10.1385/MN:24:1-3:169

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