Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection

Pfeffer, Klaus; Matsuyama, Tomohiro; Kündig, Thomas M.; Wakeham, Andrew; Kishihara, Kenji; Shahinian, Arda; Wiegmann, Katja; Ohashi, Pamela S.; Krönke, Martin; Mak, Tak W.

doi:10.1016/0092-8674(93)90134-c

Cited by 1,596 publications

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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%

“…One of the most critical physiological functions of TNF has been in host defense against intracellular bacteria, a function associated with signaling through the p55TNFR [38,57]. TNF-deficient mice readily succumb to infections with comparatively low titers of either LM [31] or Mycobacterium tuberculosis [57], while normal mice are highly resistant.…”

Section: Tmtnf Supports Host Defenses Against Listeria Monocytogenes mentioning

confidence: 99%

“…Most importantly, we have observed that in Tnf tm/tm mice, secondary lymphoid organ function is also impaired and, like TNFdeficient mice, efficient and sustained anti-SRBC Ab responses cannot be established. Together with the Ruuls et al data, the present study therefore indicates that tmTNF is not sufficient to support secondary lymphoid organ structure and function and that soluble rather than tmTNF may be required for this function.One of the most critical physiological functions of TNF has been in host defense against intracellular bacteria, a function associated with signaling through the p55TNFR [38,57]. TNF-deficient mice readily succumb to infections with comparatively low titers of either LM [31] or Mycobacterium tuberculosis [57], while normal mice are highly resistant.…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Tmtnf Supports Host Defenses Against Listeria Monocytogenes mentioning

confidence: 99%

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confidence: 99%

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

et al. 2006

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“…The TNF-␣, lymphotoxin ␣ (LT␣), and LT␤ genes and their receptors have been disrupted. [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] The results obtained demonstrate a previously unrealized role for these cytokines in peripheral lymphoid organ development. TNF-␣ Ϫ/Ϫ mice have expanded marginal zones in the spleen but are deficient in follicles and follicular dendritic cells, whereas LT␣ Ϫ/Ϫ mice show a more severe developmental defect, as they are missing peripheral lymph nodes and Peyer's patches (PP).…”

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confidence: 94%

Lymphoid abnormalities in CD40 ligand transgenic mice suggest the need for tight regulation in gene therapy approaches to hyper immunoglobulin M (IgM) syndrome

et al. 2000

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Mutations in the CD40 ligand (CD40L) are responsible for human hyper immunoglobulin M (IgM) syndrome. The absence of the interaction between CD40L, expressed by T lymphocytes, and the CD40 receptor present on the surface of B cells is responsible for the inability of B cells to carry out the isotype switch from IgM to the other Ig classes. This leads to a fatal immunodeficiency for which no cure exists. For these reasons, the CD40L gene is a good candidate for gene therapy studies. To investigate the possible effects of the expression of this tightly regulated gene in vivo, we produced transgenic mice in which CD40L expression was deregulated. Widespread ectopic expression appears to be lethal. Overexpression in mature T cells is compatible with life, but in one-third of the cases, mice developed atypical lymphoid proliferations which, occasionally, progressed into frank lymphomas. Even though gene therapy is one of the most promising approaches to cure human hyper IgM syndrome, these results suggest that when we modify very tightly regulated genes such as cytokines or other growth factors, particular care has to be taken to avoid excessive stimulation of the target cells.

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“…Nuclear extracts from 10 8 cells per point were prepared exactly as previously described (Pfe er et al, 1993). The protein concentration was measured using the bicinchoninic acid assay (BCA; Pierce, Rockford, IL) with bovine serum albumin as the standard.…”

Section: Electrophoretic Mobility Shift Assay (Emsa)mentioning

confidence: 99%

Role of p53 in aziridinylbenzoquinone-induced p21waf1 expression

Hohenstein

Park

et al. 1998

Oncogene

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Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection

Cited by 1,596 publications

References 59 publications

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

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

Lymphoid abnormalities in CD40 ligand transgenic mice suggest the need for tight regulation in gene therapy approaches to hyper immunoglobulin M (IgM) syndrome

Role of p53 in aziridinylbenzoquinone-induced p21waf1 expression

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