Impaired On/Off Regulation of TNF Biosynthesis in Mice Lacking TNF AU-Rich Elements

Kontoyiannis, Dimitris L.; Pasparakis, Manolis; Pizarro, Theresa T.; Cominelli, Fabio; Kollias, George

doi:10.1016/s1074-7613(00)80038-2

Cited by 1,266 publications

(1,300 citation statements)

References 51 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: 98%

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: 98%

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

et al. 2006

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“…The JNK group is activated by exposure of cells to cytokines and to environmental stress (for review, Whitmarsh & Davis, 1996). JNK isoforms, encoded by three genes, phosphorylate-specific sites (serines 63 and 73) on the amino-transactivation domain of cjun following exposure to ultra-violet (UV) irradiation, growth factors or cytokines (Devary et al, 1992;Kallunki et al, 1994;Kontoyiannis et al, 1999). JNK-1 and JNK-2 have been identified in the lungs of mammals, while JNK-3 has been located to the brain .…”

Section: Introductionmentioning

confidence: 99%

Allergen‐induced inflammation and airway epithelial and smooth muscle cell proliferation: role of Jun N‐terminal kinase

Eynott

Nath

Leung

et al. 2003

British J Pharmacology

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1 Chronic cellular inflammation and airway wall remodelling with subepithelial fibrosis and airway smooth muscle (ASM) cell hyperplasia are features of chronic asthma. Jun N-terminal kinase (JNK) may be implicated in these processes by regulating the transcriptional activity of activator protein (AP)-1. 2 We examined the effects of an inhibitor of JNK, SP600125 (anthra [1,9-cd] pyrazole-6 (2 H)-one), in a model of chronic allergic inflammation in the rat. 3 Rats sensitised to ovalbumin (OA) were exposed to OA-aerosol every third day on six occasions and were treated with SP600125 (30 mg kg À1 b.i.d; 360 mg in total) for 12 days, starting after the second through to the sixth OA exposure. We measured eosinophilic and T-cell inflammation in the airways, proliferation of ASM cells and epithelial cells by incorporation of bromodeoxyuridine (BrdU), and bronchial responsiveness to acetylcholine. 4 SP600125 significantly reduced the number of eosinophils (Po0.05) and lymphocytes (Po0.05) in bronchoalveolar lavage fluid, suppressed eosinophilic (Po0.05) and CD 2 þ T-cell (Po0.05) infiltration within the bronchial submucosa, and the increased DNA incorporation in ASM (Po0.05) and epithelial cell incorporation (Po0.05). 5 SP600125 did not alter bronchial hyper-responsiveness observed after chronic allergen exposure. 6 Pathways regulated by JNK positively regulate ASM cell proliferation and allergic cellular inflammation following chronic allergen exposure.

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“…TNF mRNA stability is mediated by cis-acting adenosine/uridine-rich elements (ARE) within the 3'UTR. Deletion of ARE from the mouse genomic TNF locus results in elevated basal and LPS-induced TNF expression, chronic inflammatory arthritis and inflammatory Bowel disease [24]. COX-2 mRNA contains 3'UTR similar to those of TNF and is post-transcriptionally modulated in a similar way [17].…”

Section: Discussionmentioning

confidence: 99%

AgC10, a mucin from Trypanosoma cruzi, destabilizes TNF and cyclooxygenase‐2 mRNA by inhibiting mitogen‐activated protein kinase p38

Alcaide

Fresno

2004

Eur J Immunol

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Secretion of proinflammatory mediators by activated macrophages plays an important role in the immune response to Trypanosoma cruzi. We have previously reported that AgC10, a glycosylphosphatidylinositol-anchored mucin from T. cruzi, inhibits TNF secretion by activated macrophages (de Diego, J., Punzon, C., Duarte, M. and Fresno, M., Alteration of macrophage function by a Trypanosoma cruzi membrane mucin. J. Immunol. 1997. 159: 4983-4989). In this report we have further investigated the molecular mechanisms underlying this inhibition. AgC10 inhibited TNF, IL-10 and cyclooxygenase-2 (COX-2) synthesis by macrophages activated with LPS or LPS plus IFN-+ in a dose-dependent manner. AgC10 did not affect other aspects of macrophage activation induced by LPS, such as inducible nitric oxide synthase (iNOS) expression. AgC10 also had no effect on TNF or COX-2 transcription or the induction of their promoters but inhibited the stability of TNF and COX-2 mRNA, which are regulated post-transcriptionally by the mitogen-activated protein kinase (MAPK) p38 pathway. AgC10 was found to inhibit both the activation and the activity of p38 MAPK, since MAPK activated protein kinase-2 (MAPKAP-K2 or MK-2) phosphorylation was also strongly inhibited. This led to TNF and COX-2 mRNA destabilization. In contrast, AgC10 did not affect p38 activation induced by TNF. Furthermore, AgC10 inhibition must lie upstream in the MAPK activation pathway by LPS, since this mucin also inhibited extracellularly regulated kinase (ERK) and Jun kinase (JNK) activation.

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Impaired On/Off Regulation of TNF Biosynthesis in Mice Lacking TNF AU-Rich Elements

Cited by 1,266 publications

References 51 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

Allergen‐induced inflammation and airway epithelial and smooth muscle cell proliferation: role of Jun N‐terminal kinase

AgC10, a mucin from Trypanosoma cruzi, destabilizes TNF and cyclooxygenase‐2 mRNA by inhibiting mitogen‐activated protein kinase p38

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