A Pathogenetic Role for TNFα in the Syndrome of Cachexia, Arthritis, and Autoimmunity Resulting from Tristetraprolin (TTP) Deficiency

Taylor, Gregory A.; Carballo, E.; Lee, David M.; Lai, Wi S.; Thompson, Michael J.; Patel, Dhavalkumar D.; Schenkman, Daniel I.; Gilkeson, Gary S.; Broxmeyer, Hal E.; Haynes, Barton F.; Blackshear, Perry J.

doi:10.1016/s1074-7613(00)80411-2

Cited by 723 publications

(895 citation statements)

References 18 publications

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“…In support of such a homeostatic mechanism, we have additionally observed that physiological membrane TNF expression is maintained also in cases where soluble TNF production is up-regulated such as in the case of the TTP-deficient model of TNF overexpression (Fig. 6) [45]. A relevant question that remains to be addressed is whether the TNF D1-12 mutant binds with the same affinity as the WT transmembrane TNF to TNFR1 and TNFR2.…”

Section: Discussionmentioning

confidence: 60%

“…Such a protein is tristetraprolin (TTP), which binds to TNF3 0 ARE in an inducible fashion and promotes the rapid degradation of TNF mRNA. Mice with targeted deletions of this molecule express high levels of TNF mRNA and develop a TNFdependant-arthritic phenotype [45][46][47]. We hypothesized that the increased levels of endogenous TNF mRNA resulting from the absence of TTP would allow us to directly address the efficacy of tmTNF to induce the arthritic phenotype.…”

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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: Discussionmentioning

confidence: 60%

mentioning

confidence: 99%

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

et al. 2006

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“…The activation of p38 results in the phosphorylation of several intracellular substrates, including MapKapK-2 kinase and the activating transcription factor 2 (Waskiewicz and Cooper, 1995;Obata et al, 2000). As previously described, TTP promotes TNFa mRNA instability in mouse macrophages through direct interactions with its ARE (Taylor et al, 1996a;Carballo et al, 1997Carballo et al, , 1998Carballo et al, , 2000. It has recently been shown that TTP activation requires phosphorylation by p38 (Zhu et al, 2001).…”

Section: Regulation Of Are-binding Proteinsmentioning

confidence: 82%

“…TTP binds to 14-3-3 proteins, the binding being largely dependent upon a specific site in the TTP C terminus, and the interaction between TTP and 14-3-3 proteins is biologically significant in determining cytoplasmic localization. Mice deficient in TTP develop a complex phenotype consisting of cachexia, dermatitis, conjunctivitis, destructive arthritis, myeloid hyperplasia, and autoimmunity (Taylor et al, 1996a). Virtually, all aspects of this phenotype can be prevented by the repeated injection of antibodies to TNFa, implicating an effective excess of circulating TNFa in the pathogenesis of this condition.…”

Section: Tristetraprolinmentioning

confidence: 99%

Post‐transcriptional regulation of gene expression by degradation of messenger RNAs

Bevilacqua

Ceriani

Capaccioli

et al. 2003

Journal Cellular Physiology

294

259

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Recent evidence suggests that gene expression may be regulated, at least in part, at post-transcriptional level by factors inducing the extremely rapid degradation of messenger RNAs. These factors include reactions between adenyl-uridyl-rich elements (AREs) of the relevant mRNA and either specific proteins that bind to these elements or exosomes. This review deals with examples of the proteins (AU-rich binding proteins, AUBPs) and exosomes, which have been shown to form complexes with AREs and bring about rapid degradation of the relevant mRNA, and with certain other factors, which protect the RNA from such degradation. The biochemical and physiological factors underlying the stability of messenger RNAs carrying the ARE motifs will be reviewed in the light of their emerging significance for cell physiology, human pathology, and molecular medicine. We also consider the possible application of the results of recent insights into the mechanisms to pharmacological interventions to prevent or cure disorders, especially developmental disorders, which the suppression of gene expression may bring about. Molecular targeting of specific steps in protein degradation by synthetic compounds has already been utilized for the development of pharmacological therapies.

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“…Another study demonstrates that MCPIP1 knockout mice shows severe anemia and immune disorder (Matsushita et al, 2009). This phenomenon has also been found in other CCCH zinc-finger-containing proteins such as tristetraprolin (TTP) and Roquin (Taylor et al, 1996;Vinuesa et al, 2005;Yu et al, 2007). Recently, numerous studies have focused on the RNase activity of MCPIP1 targeting on the mRNAs of IL-6, IL-1β (Matsushita et al, 2009;Mizgalska et al, 2009), and pre-microRNAs (Suzuki et al, 2011).…”

Section: Introductionmentioning

confidence: 75%

MCP-1-induced protein-1, an immune regulator

Peng

et al. 2012

Protein Cell

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MCP-1-induced protein-1 (MCPIP1) is a newly identified protein that is crucial to immune regulation. Mice lacking MCPIP1 gene suffer from severe immune disorders, and most of them cannot survive longer than 12 weeks. Considerable progress has been made in revealing the mechanism underlying the immune regulatory function of MCPIP1. MCPIP1 can act as an RNase to promote the mRNA degradation of some inflammatory cytokines, such as IL-6 and IL-1. Pre-microRNAs are also confirmed to be the substrate of MCPIP1 RNase. The structure of MCPIP1 N-terminal conserved domain shows a PilT N-terminus-like RNase structure, further supporting the notion that MCPIP1 has RNase activity. MCPIP1 can also deubiquitinate TNF receptor-associated factor family proteins, which are known to mediate immune and inflammatory responses. In this review, we summarize recent progress on the immune regulatory role of MCPIP1 and discuss the mechanisms underlying its function.

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A Pathogenetic Role for TNFα in the Syndrome of Cachexia, Arthritis, and Autoimmunity Resulting from Tristetraprolin (TTP) Deficiency

Cited by 723 publications

References 18 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

Post‐transcriptional regulation of gene expression by degradation of messenger RNAs

MCP-1-induced protein-1, an immune regulator

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