Crucial role of tumor necrosis factor (TNF) receptor 2 and membrane-bound TNF in experimental cerebral malaria

Rudolf Lucas, Pierre Juillard, Els Decoster, Mireille Redard, Danielle Burger, Yves Donati, Christine Giroud, Christine Monso-Hinard, Toon De Kesel, Wim A. Buurman, Mark W. Moore, Jean Michel Dayer, Walter Fiers, Horst Bluethmann, Georges E. Grau

Research output: Contribution to journalArticle

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Abstract

Tumor necrosis factor (TNF) has been implicated in the pathogenesis of experimental cerebral malaria (CM), but the respective role of its two types of receptors has not been established. A significant increase in the expression of TNF-receptor 2 (TNFR2, p75), but not of TNFR1 (p55), was found on brain microvessels at the time of CM in susceptible animals. Moreover, mice genetically deficient for TNFR2 (Tnfr2°) were significantly protected from experimental CM, in contrast to TNFR1-deficient (Tnfr1°) mice, which were as susceptible as wild type mice. To identify the factors involved in the protection from CM conferred by the lack of TNFR2, we assessed in both knockout and control mice the serum concentrations of mediators that are critical for the development of CM, as well as the up-regulation of intercellular adhesion molecule-1 (ICAM-1) in the brain microvessels. No significant difference in serum levels of TNF and interferon-γ was found between infected wild-type and Tnfr1°or Tnfr2°mice. Interestingly, the pronounced ICAM-1 up-regulation and leukocyte sequestration, typically occurring in brain microvessels of CM-susceptible animals, was detected in infected control and Tnfr1°mice - both of which developed CM - whereas no such ICAM-1 up-regulation or leukocyte sequestration was observed in Tnfr2°mice, which were protected from CM. Making use of microvascular endothelium cells (MVEC) isolated from wild-type, Tnfr1°or Tnfr2°mice, we show that soluble TNF requires the presence of both TNF receptors, whereas membrane-bound TNF only needs TNFR2 for TNF-mediated ICAM-1 upregulation in brain MVEC. Thus, only in MVEC lacking TNFR2, neither membrane-bound nor soluble TNF cause the up-regulation of ICAM-1 in vitro. In conclusion, these results indicate that the interaction between membrane TNF and TNFR2 is crucial in the development of this neurological syndrome.

Original languageEnglish (US)
Pages (from-to)1719-1725
Number of pages7
JournalEuropean Journal of Immunology
Volume27
Issue number7
DOIs
StatePublished - Jan 1 1997
Externally publishedYes

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Receptors, Tumor Necrosis Factor, Type II
Cerebral Malaria
Tumor Necrosis Factor-alpha
Intercellular Adhesion Molecule-1
Membranes
Up-Regulation
Microvessels
Receptors, Tumor Necrosis Factor, Type I
Endothelium
Brain
Leukocytes
Tumor Necrosis Factor Receptors
Serum
Knockout Mice
Interferons

Keywords

  • Cerebral malaria
  • Knockout mouse
  • Membrane-bound tumor necrosis factor
  • Tumor necrosis factor receptor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Crucial role of tumor necrosis factor (TNF) receptor 2 and membrane-bound TNF in experimental cerebral malaria. / Lucas, Rudolf; Juillard, Pierre; Decoster, Els; Redard, Mireille; Burger, Danielle; Donati, Yves; Giroud, Christine; Monso-Hinard, Christine; De Kesel, Toon; Buurman, Wim A.; Moore, Mark W.; Dayer, Jean Michel; Fiers, Walter; Bluethmann, Horst; Grau, Georges E.

In: European Journal of Immunology, Vol. 27, No. 7, 01.01.1997, p. 1719-1725.

Research output: Contribution to journalArticle

Lucas, R, Juillard, P, Decoster, E, Redard, M, Burger, D, Donati, Y, Giroud, C, Monso-Hinard, C, De Kesel, T, Buurman, WA, Moore, MW, Dayer, JM, Fiers, W, Bluethmann, H & Grau, GE 1997, 'Crucial role of tumor necrosis factor (TNF) receptor 2 and membrane-bound TNF in experimental cerebral malaria', European Journal of Immunology, vol. 27, no. 7, pp. 1719-1725. https://doi.org/10.1002/eji.1830270719
Lucas, Rudolf ; Juillard, Pierre ; Decoster, Els ; Redard, Mireille ; Burger, Danielle ; Donati, Yves ; Giroud, Christine ; Monso-Hinard, Christine ; De Kesel, Toon ; Buurman, Wim A. ; Moore, Mark W. ; Dayer, Jean Michel ; Fiers, Walter ; Bluethmann, Horst ; Grau, Georges E. / Crucial role of tumor necrosis factor (TNF) receptor 2 and membrane-bound TNF in experimental cerebral malaria. In: European Journal of Immunology. 1997 ; Vol. 27, No. 7. pp. 1719-1725.
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AU - Burger, Danielle

AU - Donati, Yves

AU - Giroud, Christine

AU - Monso-Hinard, Christine

AU - De Kesel, Toon

AU - Buurman, Wim A.

AU - Moore, Mark W.

AU - Dayer, Jean Michel

AU - Fiers, Walter

AU - Bluethmann, Horst

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N2 - Tumor necrosis factor (TNF) has been implicated in the pathogenesis of experimental cerebral malaria (CM), but the respective role of its two types of receptors has not been established. A significant increase in the expression of TNF-receptor 2 (TNFR2, p75), but not of TNFR1 (p55), was found on brain microvessels at the time of CM in susceptible animals. Moreover, mice genetically deficient for TNFR2 (Tnfr2°) were significantly protected from experimental CM, in contrast to TNFR1-deficient (Tnfr1°) mice, which were as susceptible as wild type mice. To identify the factors involved in the protection from CM conferred by the lack of TNFR2, we assessed in both knockout and control mice the serum concentrations of mediators that are critical for the development of CM, as well as the up-regulation of intercellular adhesion molecule-1 (ICAM-1) in the brain microvessels. No significant difference in serum levels of TNF and interferon-γ was found between infected wild-type and Tnfr1°or Tnfr2°mice. Interestingly, the pronounced ICAM-1 up-regulation and leukocyte sequestration, typically occurring in brain microvessels of CM-susceptible animals, was detected in infected control and Tnfr1°mice - both of which developed CM - whereas no such ICAM-1 up-regulation or leukocyte sequestration was observed in Tnfr2°mice, which were protected from CM. Making use of microvascular endothelium cells (MVEC) isolated from wild-type, Tnfr1°or Tnfr2°mice, we show that soluble TNF requires the presence of both TNF receptors, whereas membrane-bound TNF only needs TNFR2 for TNF-mediated ICAM-1 upregulation in brain MVEC. Thus, only in MVEC lacking TNFR2, neither membrane-bound nor soluble TNF cause the up-regulation of ICAM-1 in vitro. In conclusion, these results indicate that the interaction between membrane TNF and TNFR2 is crucial in the development of this neurological syndrome.

AB - Tumor necrosis factor (TNF) has been implicated in the pathogenesis of experimental cerebral malaria (CM), but the respective role of its two types of receptors has not been established. A significant increase in the expression of TNF-receptor 2 (TNFR2, p75), but not of TNFR1 (p55), was found on brain microvessels at the time of CM in susceptible animals. Moreover, mice genetically deficient for TNFR2 (Tnfr2°) were significantly protected from experimental CM, in contrast to TNFR1-deficient (Tnfr1°) mice, which were as susceptible as wild type mice. To identify the factors involved in the protection from CM conferred by the lack of TNFR2, we assessed in both knockout and control mice the serum concentrations of mediators that are critical for the development of CM, as well as the up-regulation of intercellular adhesion molecule-1 (ICAM-1) in the brain microvessels. No significant difference in serum levels of TNF and interferon-γ was found between infected wild-type and Tnfr1°or Tnfr2°mice. Interestingly, the pronounced ICAM-1 up-regulation and leukocyte sequestration, typically occurring in brain microvessels of CM-susceptible animals, was detected in infected control and Tnfr1°mice - both of which developed CM - whereas no such ICAM-1 up-regulation or leukocyte sequestration was observed in Tnfr2°mice, which were protected from CM. Making use of microvascular endothelium cells (MVEC) isolated from wild-type, Tnfr1°or Tnfr2°mice, we show that soluble TNF requires the presence of both TNF receptors, whereas membrane-bound TNF only needs TNFR2 for TNF-mediated ICAM-1 upregulation in brain MVEC. Thus, only in MVEC lacking TNFR2, neither membrane-bound nor soluble TNF cause the up-regulation of ICAM-1 in vitro. In conclusion, these results indicate that the interaction between membrane TNF and TNFR2 is crucial in the development of this neurological syndrome.

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