Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis.

Keffer, Jeanne; Probert, Lesley; Cazlaris, Haris; Georgopoulos, Spiros; Kaslaris, E; Kioussis, Dimitris; Kollias, George

doi:10.1002/j.1460-2075.1991.tb04978.x

Cited by 1,472 publications

(1,189 citation statements)

References 47 publications

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“…Earlier studies with TNF-deficient animals demonstrated the critical role of TNF in mediating anti-bacterial host defenses and supporting development of secondary lymphoid organ structure and function [31,42]. In further studies, Tg overexpression of TNF revealed its crucial involvement in the pathogenesis of arthritis [52] and Crohn's-like inflammatory bowel disease [53]. With reference to autoimmune disease pathogenesis, in various animal models of autoimmunity, the role of TNF is shown to be both proinflammatory and immuneor disease-suppressive [34].…”

Section: Discussionmentioning

confidence: 96%

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: Discussionmentioning

confidence: 96%

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

et al. 2006

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“…Inhibition of RANKL via OPG at the time of disease onset can prevent bone erosion (18). In addition, in a model of TNF␣-induced arthritis, OPG treatment is beneficial in terms of cartilage destruction, without affecting inflammation (60,61). Moreover, osteoclast numbers have been found to be significantly reduced in animals treated with OPG.…”

Section: Animal Modelsmentioning

confidence: 99%

“…Moreover, osteoclast numbers have been found to be significantly reduced in animals treated with OPG. Therefore, the TNF␣-triggered joint destruction is dependent on the expression of RANKL, and OPG seems to be an effective therapeutic tool for the prevention of TNF␣-mediated destruction (61,62).…”

Section: Animal Modelsmentioning

confidence: 99%

The RANK/RANKL/osteoprotegerin system in rheumatoid arthritis: New insights from animal models

Neumann

Müller‐Ladner

2005

Arthritis & Rheumatism

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“…TNF was implicated in the pathogenesis of a localized autoimmune disease with the demonstration that transgenic mice expressing human TNF coupled to the 3 0 untranslated region of b globin developed a striking polyarthritis. 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.…”

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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Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis.

Cited by 1,472 publications

References 47 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

The RANK/RANKL/osteoprotegerin system in rheumatoid arthritis: New insights from animal models

Is there a future for TNF promoter polymorphisms?

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