Mice lacking the tumour necrosis factor receptor 1 are resistant to IMF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes

Rothe, Joachim; Lesslauer, Werner; Lötscher, Hansruedi; Lang, Yolande; Koebel, Pascale; Köntgen, Frank; Althage, Alana; Zinkernagel, Rolf M.; Steinmetz, Michael; Bluethmann, Horst

doi:10.1038/364798a0

Cited by 1,201 publications

(804 citation statements)

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“…Previous studies have also suggested that TNF- § in combination with or without IFN-+ plays an important role in activating resident macrophages to kill intracellular pathogens such as L. monocytogenes and T. gondii [4, [38][39][40][41][42]. However, no correlation was observed between the increase of resistance and in vitro TNF- § production in this study (Fig.…”

Section: Discussioncontrasting

confidence: 57%

“…5D, left panel). Besides IFN-+ , other cytokines such as TNF- § have also been proposed to be an important factor in resistance to intracellular pathogens [4, [38][39][40][41][42]. However, in contrast to IFN-+ , substantial levels of TNF- § were produced by + c -/-(y) -Rag-2 -/-splenocytes with or without exogenous APC fractions in response to L. monocytogenes, and no apparent correlation was observed between the amounts of TNF- § and the susceptibility to L. monocytogenes (Fig.…”

Section: Adoptive Transfer Of Ifn-q -Producing Apc Provides Resistancmentioning

confidence: 99%

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In vivo role of IFN‐γ produced by antigen‐presenting cells in early host defense against intracellular pathogens

et al. 2003

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Antigen-presenting cells (APC), including dendritic cells and macrophages, produce a large amount of interferon (IFN)-+ , a crucial cytokine for the control of infectious diseases. To elucidate the role of IFN-+ from APC in vivo, we employed cytokine receptor common + subunit ( + c) and recombination-activating gene (Rag)-2 double-knockout ( + c -/-(y) -Rag-2 -/-) mice, which are severely impaired in IFN-+ production and are extremely susceptible to infection of intracellular pathogens including Listeria monocytogenes and Toxoplasma gondii. Adoptive transfer of IFN-+ -producing APC increased levels of serum IFN-+ and the resistance to Listeria. Although depletion of NK cells from Rag-2 -/-mice slightly increased the susceptibility to bacterial infection, they are substantially more resistant than + c -/-(y) -Rag-2 -/-mice, which are also devoid of all lymphoid cells. These results demonstrate that the APC-derived IFN-+ contributes to the control of infectious agents in vivo.

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Section: Discussioncontrasting

confidence: 57%

Section: Adoptive Transfer Of Ifn-q -Producing Apc Provides Resistancmentioning

confidence: 99%

In vivo role of IFN‐γ produced by antigen‐presenting cells in early host defense against intracellular pathogens

et al. 2003

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“…Only low [37], and it has been previously shown that the ensuing lethality is TNF-dependent and requires p55 TNF receptor signaling [38,39]. To analyze the respective phenotype of the generated mutant mice, Tnf +/+ , Tnf -/-and Tnf tm/tm mice were challenged with bacterial LPS/D-gal.…”

Section: Resultsmentioning

confidence: 99%

“…Earlier studies addressed the critical role of WT or memTNF D1-9,K11E and of TNF receptors in antibacterial host defenses [31,38,39,43,44]. To determine the role of mutant tmTNF D1-12 protein in host defense mechanisms we measured the survival of Tnf +/+ , Tnf -/-and Tnf tm/tm mice following challenge with a high and a low dose of Listeria monocytogenes (LM).…”

Section: Tmtnf Supports Host Defenses Against Listeria Monocytogenes mentioning

confidence: 99%

Transmembrane TNF protects mutant mice against intracellular bacterial infections, chronic inflammation and autoimmunity

et al. 2006

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Using targeted mutagenesis in mice, we have blocked shedding of endogenous murine TNF by deleting its cleavage site. Mutant mice produce physiologically regulated levels of transmembrane TNF (tmTNF), which suffice to support thymocyte proliferation but cannot substitute for the hepatotoxic activities of wild-type TNF following LPS/Dgalactosamine challenge in vivo and are not sufficient to support secondary lymphoid organ structure and function. Notably, however, tmTNF is capable of exerting antiListerial host defenses while remaining inadequate to mediate arthritogenic functions, as tested in the tristetraprolin-deficient model of TNF-dependent arthritis. Most interestingly, in the EAE model of autoimmune demyelination, tmTNF suppresses disease onset and progression and retains the autoimmune suppressive properties of wild-type TNF. Together, these results indicate that tmTNF preserves a subset of the beneficial activities of TNF while lacking detrimental effects. These data support the hypothesis that selective targeting of soluble TNF may offer several advantages over complete blockade of TNF in the treatment of chronic inflammation and autoimmunity.Supporting information for this article is available at: http://www.wiley-vch.de/contents/jc_2040/2006/35921_s.pdf IntroductionOriginally identified as an endotoxin-induced serum factor that causes necrosis of tumors [1] and/or cachexia [2], TNF is currently known to mediate a wide array of biological activities [3, 4]. TNF is produced in response to bacterial toxins, inflammatory products and other stimuli mainly by cells of the myeloid lineage, with additional producers including B and T lymphocytes, NK cells, microglia, astrocytes and adipocytes [3]. TNF is bioactive both as a transmembrane protein and as a homotrimeric secreted molecule [5] and mediates its effects through two distinct TNF receptors, p55TNFR (TNFRI) and p75TNFR (TNFRII) [6]. Transmembrane TNF (tmTNF) appears superior to soluble TNF in activating the p75TNFR, while at physiological concentrations soluble TNF primarily activates the p55TNFR [7]. The two types of TNF receptors share structural homology in the extracellular TNF-binding domains, but they induce separate cytoplasmic signaling pathways following receptor-ligand interaction [8]. Apoptosis and activation of NF-jB are initiated by p55TNFR, whereas p75TNFR appears to play a direct role in only a limited number of TNF responses [6,9]. Several functionally diverse proteins, such as growth factors and cytokines and including TNF, are initially synthesized as biologically active membrane-anchored molecules that are subsequently released from the cell by proteolysis [10]. Thus, surface localization may serve to restrict activity to specific microenvironments, whereas release may lead to distal effects. TNF is synthesized as a 26 kDa type II transmembrane molecule, which can be processed by a TNF-alpha converting enzyme (TACE or ADAM17), to generate secreted 17 kDa monomers that form biologically active homotrimers [11,12]. Indications for a r...

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“…2 TNF knockout mice showed that TNF is essential in resistance to infectious disease. 3 That these findings were relevant to human autoimmune/inflammatory diseases is evidenced by the high efficacy of anti-TNF antibodies (Infliximab) and recombinant soluble chimeric receptor in treating rheumatoid arthritis (RA) and Crohn's disease. 4,5 More recently, their significance was further highlighted in human infectious disease, when the observation was made that in patients treated with Infliximab, reactivation and a severe course of tuberculosis is strongly over-represented 6 These latter findings indicate an important role for TNF in controlling M. tuberculosis and most probably other intracellular infections in humans.…”

Section: Introductionmentioning

confidence: 99%

Is there a future for TNF promoter polymorphisms?

2004

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The in vitro study of TNF promoter polymorphism (SNP) function was stimulated by the numerous case-control (association) studies of the polymorphisms in relation to human disease and the appearance of several studies claiming to show a functional role for these SNPs provided a further impetus to researchers interested in the role of TNF in their disease of interest. In this review we consider case-control studies, concentrating on the autoimmune and inflammatory diseases rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, and asthma, and on infectious diseases including malaria, hepatitis B and C infection, leprosy and sepsis/septic shock. We also review the available evidence on the functional role of the various TNF promoter polymorphisms. In general, case-control studies have produced mixed results, with little consensus in most cases on whether any TNF polymorphisms are actually associated with disease, although results have been more consistent in the case of infectious diseases, particularly malaria. Functional studies have also produced mixed results but recent work suggests that the much studied À308G/A polymorphism is not functional, while the function of other TNF polymorphisms remains controversial. Studies of the TNF region are increasingly using extended haplotypes that can better capture the variation of the MHC region.

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Mice lacking the tumour necrosis factor receptor 1 are resistant to IMF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes

Cited by 1,201 publications

References 28 publications

In vivo role of IFN‐γ produced by antigen‐presenting cells in early host defense against intracellular pathogens

In vivo role of IFN‐γ produced by antigen‐presenting cells in early host defense against intracellular pathogens

Transmembrane TNF protects mutant mice against intracellular bacterial infections, chronic inflammation and autoimmunity

Is there a future for TNF promoter polymorphisms?

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