Tumor necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases.

Sofia Xanthoulea; Manolis Pasparakis; Stavroula Kousteni; Cord Brakebusch; David Wallach; Jan Bauer; Hans Lassmann; George Kollias

doi:10.1084/jem.20040435

Tumor necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases.

Sofia Xanthoulea, Manolis Pasparakis, Stavroula Kousteni, Cord Brakebusch, David Wallach, Jan Bauer, Hans Lassmann, George Kollias

Biomedicinsk Institut

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

165 Citationer (Scopus)

Abstract

Udgivelsesdato: 2004-Aug-2

Originalsprog	Engelsk
Tidsskrift	Journal of Experimental Medicine
Vol/bind	200
Udgave nummer	3
Sider (fra-til)	367-76
Antal sider	9
ISSN	0022-1007
DOI	https://doi.org/10.1084/jem.20040435
Status	Udgivet - 2004

Bibliografisk note

Keywords: Amino Acid Sequence; Animals; Antigens, CD; Arthritis; Encephalomyelitis, Autoimmune, Experimental; Hepatitis, Chronic; Immunity, Natural; Lipopolysaccharides; Listeria Infections; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Tumor Necrosis Factor-alpha

Adgang til dokumentet

10.1084/jem.20040435

Citationsformater

Xanthoulea, S., Pasparakis, M., Kousteni, S., Brakebusch, C., Wallach, D., Bauer, J., Lassmann, H., & Kollias, G. (2004). Tumor necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases. Journal of Experimental Medicine, 200(3), 367-76. https://doi.org/10.1084/jem.20040435

Tumor necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases. / Xanthoulea, Sofia; Pasparakis, Manolis; Kousteni, Stavroula; Brakebusch, Cord; Wallach, David; Bauer, Jan; Lassmann, Hans; Kollias, George.

I: Journal of Experimental Medicine, Bind 200, Nr. 3, 2004, s. 367-76.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Xanthoulea, S, Pasparakis, M, Kousteni, S, Brakebusch, C, Wallach, D, Bauer, J, Lassmann, H & Kollias, G 2004, 'Tumor necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases.', Journal of Experimental Medicine, bind 200, nr. 3, s. 367-76. https://doi.org/10.1084/jem.20040435

Xanthoulea, Sofia ; Pasparakis, Manolis ; Kousteni, Stavroula ; Brakebusch, Cord ; Wallach, David ; Bauer, Jan ; Lassmann, Hans ; Kollias, George. / Tumor necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases. I: Journal of Experimental Medicine. 2004 ; Bind 200, Nr. 3. s. 367-76.

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title = "Tumor necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases.",

abstract = "Tumor necrosis factor (TNF) is a potent cytokine exerting critical functions in the activation and regulation of immune and inflammatory responses. Due to its pleiotropic activities, the amplitude and duration of TNF function must be tightly regulated. One of the mechanisms that may have evolved to modulate TNF function is the proteolytic cleavage of its cell surface receptors. In humans, mutations affecting shedding of the p55TNF receptor (R) have been linked with the development of the TNFR-associated periodic syndromes, disorders characterized by recurrent fever attacks and localized inflammation. Here we show that knock-in mice expressing a mutated nonsheddable p55TNFR develop Toll-like receptor-dependent innate immune hyperreactivity, which renders their immune system more efficient at controlling intracellular bacterial infections. Notably, gain of function for antibacterial host defenses ensues at the cost of disbalanced inflammatory reactions that lead to pathology. Mutant mice exhibit spontaneous hepatitis, enhanced susceptibility to endotoxic shock, exacerbated TNF-dependent arthritis, and experimental autoimmune encephalomyelitis. These results introduce a new concept for receptor shedding as a mechanism setting up thresholds of cytokine function to balance resistance and susceptibility to disease. Assessment of p55TNFR shedding may thus be of prognostic value in infectious, inflammatory, and autoimmune diseases.",

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AU - Xanthoulea, Sofia

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AU - Brakebusch, Cord

AU - Wallach, David

AU - Bauer, Jan

AU - Lassmann, Hans

AU - Kollias, George

N1 - Keywords: Amino Acid Sequence; Animals; Antigens, CD; Arthritis; Encephalomyelitis, Autoimmune, Experimental; Hepatitis, Chronic; Immunity, Natural; Lipopolysaccharides; Listeria Infections; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Tumor Necrosis Factor-alpha

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N2 - Tumor necrosis factor (TNF) is a potent cytokine exerting critical functions in the activation and regulation of immune and inflammatory responses. Due to its pleiotropic activities, the amplitude and duration of TNF function must be tightly regulated. One of the mechanisms that may have evolved to modulate TNF function is the proteolytic cleavage of its cell surface receptors. In humans, mutations affecting shedding of the p55TNF receptor (R) have been linked with the development of the TNFR-associated periodic syndromes, disorders characterized by recurrent fever attacks and localized inflammation. Here we show that knock-in mice expressing a mutated nonsheddable p55TNFR develop Toll-like receptor-dependent innate immune hyperreactivity, which renders their immune system more efficient at controlling intracellular bacterial infections. Notably, gain of function for antibacterial host defenses ensues at the cost of disbalanced inflammatory reactions that lead to pathology. Mutant mice exhibit spontaneous hepatitis, enhanced susceptibility to endotoxic shock, exacerbated TNF-dependent arthritis, and experimental autoimmune encephalomyelitis. These results introduce a new concept for receptor shedding as a mechanism setting up thresholds of cytokine function to balance resistance and susceptibility to disease. Assessment of p55TNFR shedding may thus be of prognostic value in infectious, inflammatory, and autoimmune diseases.

AB - Tumor necrosis factor (TNF) is a potent cytokine exerting critical functions in the activation and regulation of immune and inflammatory responses. Due to its pleiotropic activities, the amplitude and duration of TNF function must be tightly regulated. One of the mechanisms that may have evolved to modulate TNF function is the proteolytic cleavage of its cell surface receptors. In humans, mutations affecting shedding of the p55TNF receptor (R) have been linked with the development of the TNFR-associated periodic syndromes, disorders characterized by recurrent fever attacks and localized inflammation. Here we show that knock-in mice expressing a mutated nonsheddable p55TNFR develop Toll-like receptor-dependent innate immune hyperreactivity, which renders their immune system more efficient at controlling intracellular bacterial infections. Notably, gain of function for antibacterial host defenses ensues at the cost of disbalanced inflammatory reactions that lead to pathology. Mutant mice exhibit spontaneous hepatitis, enhanced susceptibility to endotoxic shock, exacerbated TNF-dependent arthritis, and experimental autoimmune encephalomyelitis. These results introduce a new concept for receptor shedding as a mechanism setting up thresholds of cytokine function to balance resistance and susceptibility to disease. Assessment of p55TNFR shedding may thus be of prognostic value in infectious, inflammatory, and autoimmune diseases.

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