Dissertations / Theses on the topic 'Tumour necrosis factor receptor I'
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1
Albataineh, Eman Mohammad. "Studies of tumour necrosis factor receptor-1 in tumour necrosis factor receptor associated periodic sysndrome (TRAPS)." Thesis, University of Nottingham, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.537655.
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Björnberg, Flemming. "Processing of TNF-receptors to soluble receptor forms in myeloid cells." Lund : Dept. of Hematology, Lund University, 1998. http://catalog.hathitrust.org/api/volumes/oclc/39176479.html.
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Vagenas, Panagiotis. "Tumour necrosis factor receptor signalling pathways in chronically activated T lymphocytes." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.416631.
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Wood, Katrina Mackay. "Lymphocyte signalling through members of the Tumour Necrosis Factor Receptor family." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320268.
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Reddy, Shalini Kamu. "Tumour necrosis factor receptor superfamily memebers in chicken B cell development." Thesis, University of Bristol, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.500214.
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Kamu, Reddy Shalini. "Tumour necrosis factor receptor superfamily members in chicken B cell development." Thesis, University of Bristol, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.500863.
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Connell, Michelle C. "Role of tumour necrosis factor receptor subtypes in endothelial cell inflammatory responses." Thesis, University of Aberdeen, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.430906.
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The signalling cascade, produced after THF ligand binding, involves the recruitment of many different signalling proteins, and includes the activation of mitogen-activated protein kinase (MAPK) pathways (e.g. p42/p44 MAPK, p38 MAPK and JNK), as well as the activation of many transcription factors e.g. activating protein-1 (AP-1) and nuclear factor-kB( NF-kB) The aim of this thesis was firstly to investigate the role of TNF-a in the activation of the transcription factor AP-1. Secondly, to investigate TNFR expression in HUVEC cells and then investigates the cellular consequences of TNF treatment on HUVEC cells. Thirdly, we investigated the activation of the MAPK family and the activation of the transcription factors AP-1 and NFKB in HUVEC cells. Finally, we investigated cell adhesion molecule induction as a result of TNF stimulation in endothelial cells, and then assessed the role of MAPK family members on TNF induced induction of cell surface adhesion molecule expression. Differential activation of TNFRs was also investigated using TNF receptor specific mutant proteins (‘muteins’), to understand the role of either TNFR1 or TNFR2 in these cellular responses. The key finding of this study were that both TNF receptor subtypes were capable of activating AP-1 and NF-kB transcriptional activity in HeLa, HEK 293 or HUVEC cell systems, but to varying degrees. Huvec cells express both TNF receptor subtypes and TNF was found to result in neither death nor proliferation of endothelial cells.
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Kimberley, Fiona. "A study of the structure and function of tumour necrosis factor receptor superfamily members." Thesis, University of Oxford, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404169.
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Drewe, Elizabeth. "Molecular and therapeutic aspects of tumour necrosis factor receptor 1 associated periodic syndrome (TRAPS)." Thesis, University of Nottingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.416437.
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Tucker, S. J. "Development of novel technologies used to measure tumour necrosis factor receptor signalling in living cells." Thesis, University of Aberdeen, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.590943.
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The aim of this work was firstly to assess novel reporter constructs as potential methods for investigating TNF signalling. The key early findings of this study suggested the GFP-linked reporter construct system as more suitable for studying TNF signalling. Subsequently a series of optimisation experiments maximised this system in HeLa and TF-1 cells. In both cell lines TNF strongly induced p38 MAPK, p42/44 MAPK, JNK and NF-κB reporter constructs. In functional terms p42/44 MAPK activation was shown to be critical for TF-1 cell proliferation, whilst JNK related to TNF-induced cell death in both cell types. Interestingly, p38 MAPK was also related to TNF-induced cell death, but only in TF-1 cells. In contrast, NF-κB were shown to exist in a co-inhibitory relationship, in which inhibition of one resulted in potentiation of the other. This was shown to be an important regulatory controller of cell death following TNF stimulation of HeLa and TF-1 cells. In addition, TNF-induced JNK activation was related to caspases, with suppression of caspases reducing the degree of JNK activity. Finally, receptor constructs were used to assess the signalling prowess of sodium salicylate in TF-1 cells, which activated the same signal pattern as TNF in dying TF-1 cells. Indeed sodium salicylate reciprocated the selective induction of cell death in proliferating TF-1 cells seen with TNF, suggesting potential for this drug in the treatment of leukaemia. Associated with early experiments, polymeric sponge toxin fractions (polyAPS and halitoxin) were shown to mediate successful HEK 293 and HeLa transfection on account of their porative activity.
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Prendergast, D. "Discovery of tumour necrosis factor receptor-1 (p55) binding peptides using a phage display library." Thesis, Queen's University Belfast, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368468.
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Mohamed, Ahmed A. A. "Cross-talk between kinases and proteases in tumour necrosis factor-#alpha# receptor subtype-induced apoptosis." Thesis, University of Aberdeen, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.274797.
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Firstly, we demonstrated that caspase-dependent cell death was enhanced by the over-expression of the type II TNF receptor (TNFR2). HeLa cells, which naturally express high levels of type I TNF receptor (TNFR1) and low levels of TNFR2, were engineered to stably over-express TNFR2. This combined with the use of genetically-engineered mutated TNFs that preferentially activate TNFR1 or TNFR2, we showed that both receptors can induce cell death, although this process occurred predominantly through TNFR1. TNF-induced cell death was inhibited by the stable expression of cytokine response modifier A (CrmA), a potent inhibitor of receptor proximal caspases. By isolating early apoptotic cells, we were able to identify differential activation profiles of members of the mitogen-activated protein kinase (MAPK) family during TNF-induced apoptosis. In dying HeLa-TNFR2 cells, there was increased activation of c-Jun NH2-terminal kinase (JNK) while the activation levels of p38 MAPK and p42/44 MAPK remained unchanged. The use of peptidergic caspase inhibitors demonstrated that caspase-dependent modulation of JNK but not p38 MAPK or p42/44 MAPK takes place, and as such may provide a mechanism which accounts for the differences observed in MAPK activity during TNF-induced cell death. Through expression of a dominant negative upstream activator of JNK (SEK-1-AL) and a pharmacological inhibitor of JNK activity, we were able to determine the role of JNK activation in TNF receptor-mediated apoptosis. These findings clearly demonstrate that through cross-talk, TNF receptors, are able to further modulate the tightly regulate cellular consequences of TNF treatment and that JNK is a TNF-induced kinase that may play a role in the cytokine’s apoptotic cellular signalling.
13
Siebert, Stefan. "Functional characterisation of tumour necrosis factor receptor superfamily 1A (TNFRSF1A) mutations that cause systemic inflammation." Thesis, Cardiff University, 2005. http://orca.cf.ac.uk/55610/.
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This work describes a study into the effects of clinically relevant TNF receptor superfamily 1A (TNFRSF1A) mutations associated with the TNF receptor-associated periodic syndrome (TRAPS). TRAPS is a dominantly inherited autoinflammatory disorder characterised by episodes of systemic inflammation. The first part focuses on a novel TNFRSF1A mutation (C43S) from a patient with TRAPS. A primary dermal fibroblast line was established from the patient and used to study the functional effects of this TRAPS mutation. Experiments revealed that the C43S TNFRSF1A mutation resulted in reduced activation of the transcription factors NF-kB and AP-1 in fibroblasts, while production of the pro-inflammatory cytokines IL-6 and IL-8 was maintained at relatively normal levels. TNFa-induced apoptosis was also reduced in fibroblasts and peripheral blood mononuclear cells from this patient with TRAPS. TNFRSF1A shedding from neutrophils was normal. The work was extended by generating and expressing plasmids for four recombinant TNFRSF1A TRAPS mutants, including C43S, in B-cell lines by transient transfection. All four recombinant TNFRSF1A mutants resulted in reduced NF-kB activation, suggesting that reduced TNFRSF1A signalling may be general feature of TRAPS. The four TRAPS mutants all displayed reduced surface expression of TNFRSF1 A, with the receptor predominantly localised intracellularly. The signalling and expression studies also suggest that there may be subtle differences between the various TRAPS mutants. In conclusion, the TRAPS mutations studied alter TNFRSF1A expression and localisation, and reduce TNFRSF1 A-mediated signalling, revealing new insights into TNFRSF1A.
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Bertok, Szabolcs. "Tumour necrosis factor-α (TNF) receptor subtype signalling in acute lung injury : a therapeutic approach." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/29862.
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To date no definite treatment exists for acute lung injury (ALI), only supportive therapy, among which mechanical ventilation is an important tool; however ventilation itself may exacerbate the underlying injury, termed ventilator-induced lung injury (VILI). The pro-inflammatory cytokine tumour necrosis factor alpha (TNF) has been consistently implicated in the pathogenesis of ALI/VILI, however clinical trials with anti-TNF therapy failed to improve the outcome. TNF acts on two cell-surface receptors (TNFRs), p55 and p75, and knock-out studies in ALI/VILI indicate they have directly opposing roles, i.e. promoting or protecting against pulmonary oedema, respectively, but it remains unclear where these signalling mechanisms take place, being the endothelial or epithelial side of the alveolar-capillary membrane. This project had two main aims: to characterise the expression profile and roles of TNF receptor subtypes on each side of the alveolarcapillary membrane and to modulate ALI progression in mouse models by targeting individual TNFRs accordingly. Characterisation studies on freshly harvested mouse pulmonary endothelial cells (PECs) using flow cytometry indicated expression of both receptors with dominance of p55. Knock-out and pharmacological inhibition studies in vivo and in vitro, respectively, found p55 to be the major mediator of TNF-induced adhesion molecule expression on PECs, with a similar but less potent role for p75 that varied across adhesion molecules. Endotoxaemia resulted in rapid shedding of p55 on PECs while expression of p75 was preserved, indicating that the relative role of the receptors may change during inflammatory conditions. Specific inhibition of intraalveolar p55 signalling by domain antibodies significantly attenuated both pulmonary oedema and inflammation in mouse models of VILI and acid-aspiration. These data offer new, potentially clinically applicable insights into the involvement of TNFR biology in ALI and the novel domain antibody technology may open a new therapeutic approach for patients who suffer from, or at risk of ALI.
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McIntosh, Kathryn Ann. "Proteinase-activated receptor-2( PAR-2) and tumour necrosis factor-alpha ( TNFα) signalling in inflammation." Thesis, University of the West of England, Bristol, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.489251.
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Proteinase activated receptor-2 (PAR-2) is a novel G-protein coupled receptor, that is activated by means of proteolytic cleavage (Macfarlane et al, 2001) and has both pro and anti-inflammatory actions depending upon the system examined. PAR-2 have been linked to the stress-activated protein kinases (SAPKs), JNK and p38 MAP kinase and NFK13 signalling (Kanke et al, 2001; Sabri et al, 2000), pathways known to be involved in proinflammatory responses in several cell types. TNFa has been demonstrated to up-regulate PAR-2 expression in a variety of cell types (Nystedt et al, 1996; Ritchie et al, 2007). Since both TNFa and PAR-2 are implicated in inflammation, we examined the possibility of altered PAR-2 trafficking under inflammatory conditions and possible crosstalk between PAR-2 and TNFa at the level of intracellular signalling. Previous studies have characterised P AR-2 trafficking in transfected cell lines, however the effects of inflammatory stimuli on the kinetics of PAR-2 trafficking has not been investigated. The study sought to re-characterise PAR-2 trafficking in the presence of inflammatory stimuli. NCTC2544 cells transfected with YFP epitope tagged PAR-2, demonstrated clear PAR-2 expression and trafficking of the receptor was successfully characterised, however no significant differences in the kinetics of P AR-2 trafficking under inflammatory conditions compared to control was observed. The latter part of the study examined PAR-2 and TNFa mediated activation of the MAPK and NFK13 pathways. In a keratinocyte cell line stably expressing PAR-2 (CloneG), trypsin, SLIGKV-OH, and TNFa, caused a time and concentration-dependent increase in p38 MAPK and JNK phosphorylation however, preliminary results failed to show evidence of synergy between the receptors. Surprisingly however, pre-activation of P AR-2 substantially reduced the ability of TNFa to activate JNK. The inhibitory effect of P AR-2 was mimicked by the protein kinase C activator PMA, partially reversed by the PKC inhibitor GF109203X, and completely reversed by the novel Gaqlll inhibitor YM-254890, consistent with a role for both Ca2+ -dependent and independent PKC isoforms and for P AR-2 coupling to Gaq/11 to mediate this agonist driven inhibitory response. These results indicate a potential mechanistic explanation for both the anti and pro-inflammatory actions of P AR- 2, and highlight a possible novel therapeutic avenue for the development ofPAR-2 agonists as anti-inflammatory drugs.
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Jupp, Orla J. "The role of tumour necrosis factor α receptor subtypes in mediating cytosolic phospholipase A2 activation." Thesis, University of Aberdeen, 2000. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU602033.
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The TF-1 human erythroleukemic cell line exhibits opposing physiological responses towards tumour necrosis factor-alpha (TNF-alpha) treatment, dependent upon the mitotic state of the cells. Mitotically active cells respond to TNF-alpha by rapidly undergoing apoptosis whereas TNF-alpha exposure stimulates cellular proliferation in mitotically quiescent cells. These intracellular functions of TNF-alpha are transmitted by the type I (TNFR l) and type II (TNFR 2) receptors, but the signalling mechanisms elicited by these two receptors are not fully understood. We show that the expression levels of TNFR2 vary during the TF-1 cell cycle. Furthermore, studies utilising TNF-alpha receptor subtype-specific TNF-alpha mutants implicated the TNFR2 in apoptotic signalling. These data show a bifunctional physiological role for TNF-alpha in TF-1 cells that is dependent on mitotic activity and controlled by the TNFR2. To examine the role of endogenous TNFR2 in mediating TNF-induced signalling, we used KYM-1 human rhabdomyosarcoma cells, which express high levels of the TNFR2 and TNFR l. We also used HeLa human cervical epithelial cells (which express mainly TNFR l) that had been transfected with TNFR2 cDNA and thus engineered to express higher numbers of receptors than KYM-1 cells. The role of TNFR2 activation in enhanced apoptotic cell death was confirmed in these cells expressing high levels of TNFR2. It is reported here that subtype-specific differential kinase activation and cPLA 2 activation is seen in these cell models. KYM-1 and HeLa clones displayed c-Jun N-terminal kinase (JNK) activation by wild-type TNF, TNFRl-specific mutant and TNFR2-specific mutant in combination with TNFR2-specific agonistic monoclonal antisera. Moreover, alternative expression of a TNFR2 deletion mutant lacking its cytoplasmic domain rendered the cells unable to activate .INK activity through this receptor isotype. Conversely, only activation of the TNFRl could stimulate mitogen-activated protein kinase (MAPK) or p38 MAPK activities in a time-dependent manner. In addition to kinase activation cPLA2 activity (previously thought to be mediated solely by TNFRl) was also found to increase in a receptor subtype-specific manner. The TNFRl was shown to lead to the phosphorylation and activation of CPLA2, whilst the TNFR2 was implicated in translocation of cPLAi to perinuclear regions. These findings indicate that both receptors differentially modulate extracellular signal-regulated kinases and CPLA2 and that these enzymes contribute to the TNFs cytotoxic response.
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Marles-Wright, Jon. "Structural studies on determinants of receptor/ligand binding in the tumour necrosis factor and T cell receptor protein families." Thesis, University of Oxford, 2005. http://ora.ox.ac.uk/objects/uuid:1f6d480a-a641-4778-9ff0-ece1b2d38d5c.
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Protein-protein recognition plays a central role in the surveillance of self and non-self in the mammalian immune system and ultimately in cellular survival within the organism. Two systems of fundamental importance to the immune system are the Tumour Necrosis Factor (TNF) and the T cell receptor (TCR) families. High-throughput methods developed within the Oxford Protein Production Facility have been successfully applied to the production of members of the TNF receptor and ligand superfamilies for structural characterisation. The TNF receptor DR6 was successfully refolded from E.coli inclusion bodies using a rapid-dilution technique and yielded diffraction quality crystals. Data collected from these crystals will be used to obtain an x-ray crystallographic model of DR6. Vascular Endothelial Growth Inhibitor (VEGI) was produced as a soluble recombinant protein in E.coli, and formed a number of poorly diffracting crystals, it is hoped that further trials and optimization of conditions will lead to improved data quality. Lymphotoxin β receptor was produced in a Eukaryotic system. This has shed light on the complications posed by signal peptide cleavage and glycosylation on the production of protein for crystallization trials. TNF superfamily proteins are ideal targets for the design of novel therapeutic agents due to their involvement in a number of disease pathologies. Various methods of molecular docking and small molecule design were applied to the search for potential inhibitors of receptor binding for the TNF ligand proteins TRAIL and BAFF. A number of potential drug leads were identified from the National Cancer Institute drug database. The Natural Killer (NK) T cell restricted TCRs recognise CD1d-presented glycolipid. Determination of the crystal structures of the invariant NK TCR and the NK restricted TCRs 5E and 5B shows that these proteins adopt the canonical structures of class I MHC restricted TCRs. This suggests that the binding of CD1d-glycolipid by these receptors will conform to the same model of binding seen for the class I MHC restricted TCRs.
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Abrahams, Vikki Martyne. "The role of immunoglobulin receptors in the pathogenesis of rheumatoid arthritis." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314351.
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Youseff, Brian. "The Role of Tumor Necrosis Factor Receptor-Associated Factor 6 in Tick-Borne Flavivirus Infection." University of Toledo Health Science Campus / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=mco155691388498993.
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Colbert, Jeff D. "Compartmentalization of the TNF-Receptor 1-mediated signal transduction /." Connect to full text at ProQuest Digital Dissertations. IP filtered, 2005.
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Thesis (Ph.D. in Immunology) -- University of Colorado at Denver and Health Sciences Center, 2005.Typescript. Includes bibliographical references (leaves 144-178). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
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Terry, Jennifer L. "The characterization of TRUSS : a novel scaffolding protein in tumor necrosis factor-[alpha] receptor-1 signaling /." Connect to full text via ProQuest. IP filtered, 2005.
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Thesis (Ph.D. in Immunology) -- University of Colorado, 2005.Typescript. Includes bibliographical references (leaves 190-212). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
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Lobito, Adrian A. "Cell death, stomach pain and migratory rashes : structure-functional analysis of tumour necrosis factor receptor superfamily members in health and disease." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433370.
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Duthie, Susan. "Studies of acute phase proteins and tumour necrosis factor receptors as inflammatory markers in the cat." Thesis, University of Glasgow, 1999. http://theses.gla.ac.uk/4809/.
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The measurement of acute phase proteins is used by human clinicians to give valuable infonnation about a patient's inflammatory response, both when monitoring clinical disease and when assessing the effect of therapy. Levels of soluble receptors for the cytokine, tumour necrosis factor, also increase as a result of inflammatory stimuli and are useful prognostic markers over the asymptomatic phase of human immunodeficiency virus infection. The aim of the work presented in this thesis was to detennine whether these markers are of value when investigating feline disease. Reference ranges for two acute phase proteins, aI-acid glycoprotein (AGP) and haptoglobin were detennined by measuring their concentrations in serum samples from healthy cats. Analysis of samples from cats with feline infectious peritonitis (FIP) and from cats suffering from conditions with a similar clinical presentation revealed that measurement of AGP can be a useful adjunct to other laboratory tests when reaching a diagnosis. In contrast, measurement of haptoglobin was not found to be of value. Despite increases in the levels of pro-inflammatory cytokines in samples taken from cats during the asymptomatic phase of feline immunodeficiency virus (FIV) infection, no changes were detected in the levels of AGP and haptoglobin. It was concluded that these acute phase proteins are of no benefit as prognostic markers in FlY. The L929 bioassay was used to investigate anti-TNF-a activity in cell culture fluids from feline splenic cells. Cytotoxic activity was demonstrated in very few of the samples whilst anti-cytotoxic activity was detected in the majority of samples. This anti-cytotoxic activity was attributed to the presence of feline soluble TNF receptor type 1 (sTNFR-I) binding to and inhibiting the effects of TNF-a. This was not confinned because of the lack of specific neutralising antibody. Subsequent work was therefore directed towards the development of immune-based species-specific assays for feline soluble TNF receptors (sTNFRs). The polymerase chain reaction was used to amplify the sequences coding for feline sTNFRs. Most of the extracellular domain of feline TNFR-l and part of the intracellular domain of feline TNFR-2 were cloned and sequenced using this technique. The amplified regions demonstrated 85% and 77% homology at the nucleic acid level and 83% and 67% homology at the amino acid level to the corresponding regions of the human sequences for TNFR-l and 2 respectively. Feline sTNFR-l was expressed as a glutathione-S-transferase fusion protein. After purification, concentration and electrophoresis, the appropriate protein band was excised and used to inoculate a sheep. Antiserum taken from the sheep post-inoculation recognised the expressed protein by western blotting, but results were inconsistent and analysis of the antiserum was hampered by the very small amounts of expressed protein available. Two peptides were synthesised based on regions of antigenicity in feline sTNFR-l and were used to inoculate sheep. Antiserum to peptide A showed a strong reaction against peptide A in an ELISA and gave a positive result when used as the primary antibody to stain healthy feline liver tissue. In conclusion, both antiserum to expressed feline sTNFR-l and anti-peptide antibody based on a region of feline sTNFR-l have been raised in sheep and are available for the development of an assay for this protein. Further expression of feline TNFR-l will be required before these antisera can be analysed fully.
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Maney, Nicola Jayne. "The regulation of dendritic cell maturation and survival by tumour necrosis factor receptors 1 and 2." Thesis, University of Newcastle upon Tyne, 2014. http://hdl.handle.net/10443/2730.
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Dendritic cells (DC) are potent antigen presenting cells which have been implicated in a number of autoimmune diseases. Tumour necrosis factor (TNF) is a key mediator of inflammatory diseases such as rheumatoid arthritis (RA) and plays a central role in DC biology. My aim was to identify the individual contributions of the two TNF receptors (TNFR1 and TNFR2) in regulating the maturation and survival of human inflammatory monocyte-derived (moDC) and steady-state myeloid DC. To address this, I have made use of TNFR-selective ligands in order to dissect the individual contributions of the two receptors. In moDC, TNFR1-selective, but not TNFR2-selective stimulation resulted in increased expression of DC maturation markers CD83 and CD86, and enhanced T cell stimulatory capacity. A DNA binding assay was used to demonstrate that in moDC TNFR1, but not TNFR2, activates the classical p65 NFB pathway whereas both TNFR1 and TNFR2 activate the alternative p100/p52 NFB pathway, highlighting differences in signalling downstream of the receptors. Furthermore, moDC survival was prolonged by selective stimulation of either TNFR1 or TNFR2 as shown by reduced intracellular levels of active caspase-3, indicating that innate signals can promote DC survival in the absence of DC maturation. Accordingly, the p65 NFB pathway was involved in the pro-survival effect of TNFR1 whereas the Bcl-2/Bcl-xL pathway (identified by the use of small molecule inhibitors) was essential to survival mediated by both TNFR. In contrast, in myeloid DC, maturation was mainly mediated through TNFR1, whereas TNFR2 was superior in protecting DC from cell death. Antagonistic TNFR1-specific antibodies were used to confirm that cell death protection via TNFR2 was independent of TNFR1-mediated signalling and vice versa confirming that the two receptors can act independently of one another. Understanding the immunoregulatory properties of signalling through these two TNF receptors is important for the design of more targeted anti-TNF therapy.
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Lubrano, Di Ricco Martina. "The role of tumor necrosis factor receptor family (TNFRF) members in regulatory T cell biology." Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS222.
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Les lymphocytes T régulateurs CD4+ Foxp3+ (Treg) jouent un rôle essentiel dans l'homéostasie du système immunitaire et dans la prévention des maladies auto-immunes. Une meilleure connaissance de leur biologie pourrait améliorer leur utilisation en médecine. Différentes molécules apparentées composent la grande famille du TNF. Beaucoup de leurs récepteurs (famille du TNFR) sont exprimés par les cellules du système immunitaire, en particulier par les Treg. Des molécules agonistes ou inhibitrices de certains membres de la famille du TNF ou du TNFR ont un effet thérapeutique dans les maladies auto-immunes ou les cancers. Leur action pourrait impliquer les Treg. Cependant, nous avons très peu de connaissance sur l’effet direct des membres de la famille TNFR sur la biologie du Treg et sur les similitudes et les différences de leurs effets entre différents membres. Ici, nous montrons que la co-stimulation de Treg par des agonistes de TNFR2, 4-1BB, GITR ou DR3 augmente leur prolifération et leur survie in vitro. Ces Treg co-stimulés ont une expansion améliorée in vivo et une meilleure capacité à contrôler une maladie inflammatoire. L’activation de ces récepteurs induit une signature ARN similaire, suggérant que la transduction du signal est comparable. Enfin, nous montrons le rôle critique de la voie canonique NF-B dans la co-stimulation Treg induite par ces membres de la famille TNFR. Ainsi, ces molécules pourraient jouer un rôle majeur dans la biologie des Treg et une partie des effets thérapeutiques des médicaments ciblant les membres de la famille du TNF ou du TNFR pourrait impliquer les TregCD4+ Foxp3+ regulatory T cells (Tregs) play a critical role in immune homeostasis and in the prevention of autoimmune diseases by regulating immune responses, therefore a better knowledge of their biology could improve their use in medicine. Different related molecules compose the large TNF family. Many of their receptors (TNFR family) are expressed by cells of the immune system,specifically byTregs.Blocking or agonist reagents of some TNF or TNFR family members have strong potential to control autoimmune diseases or to improve anti-tumor immunity by acting on conventional T cells or Tregs. However, we know very little on the direct effect of TNFR family members on Treg biology and on similarities and differences of their effects between different members. Here, we showed that Treg co-stimulation with agonists of TNFR2, 4-1BB, GITR or DR3, but not of OX40, increased their proliferation and survival. These co-stimulated Tregs had improved expansion in vivo and increased capacity to control an inflammatory disease. Triggering these receptors induced a similar signature at the transcription level, showing that they share signal transduction. Using a DNA binding assay and loss of function approach, we showed a critical role of the canonical NF-B pathway in the Treg co-stimulation induced by these TNFR family members. Thus, these molecules may play a major role in Treg biology and part of the therapeutic effects of drugs targeting TNF or TNFR family members may be Treg-mediated
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Mukherjee, Paramita. "Tumor necrosis factor receptor gene therapy influences humoral and cellular immune responses in collagen induced arthritis." Connect to online resource - WSU on-site and authorized users, 2003.
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Glossop, John Richard. "Tumour necrosis factor and its receptors in rheumatoid arthritis : relationship between gene polymorphism, cytokine production and disease outcome." Thesis, Keele University, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.421669.
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Moquin, David M. "Elucidating the Molecular Mechanism of CYLD-Mediated Necrosis: A Dissertation." eScholarship@UMMS, 2013. https://escholarship.umassmed.edu/gsbs_diss/659.
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TNFα-induced programmed necrosis is a caspase-independent cell death program that is contingent upon the formation of a multiprotein complex termed the necrosome. The association of two of the components of the necrosome, receptor interacting protein 1 (RIP1) and RIP3, is a critical and signature molecular event during necrosis. Within this complex, both RIP1 and RIP3 are phosphorylated which are consequential for transmission of the pro-necrotic signal. Namely, it has been demonstrated that RIP3 phosphorylation is required for binding to downstream substrates. Nevertheless, the regulatory mechanisms governing necrosome activation remain unclear. Since necrosis is implicated in a variety of different diseases, understanding the biochemical signaling pathway can potentially yield future drug targets. I was interested in identifying other regulators of necrosis in hope of gaining a better understanding of the necrosis signaling pathway and regulators of the necrosome. To address this, I screened a cancer gene siRNA library in a cell line sensitive to necrosis. From this, I independently identified CYLD as a positive regulator of necrosis. Previous studies suggest that deubiquitination of RIP1 in the TNF receptor (TNFR)-1 signaling complex is a prerequisite for transition of RIP1 into the cytosol and assembly of the RIP1-RIP3 necrosome. The deubiquitinase cylindromatosis (CYLD) is presumed to promote programmed necrosis by facilitating RIP1 deubiquitination in this membrane receptor complex. Surprisingly, I found that TNFα could induce RIP1-dependent necrosis in CYLD-/- cells. I show that CYLD does not regulate RIP1 ubiquitination at the receptor complex. Strikingly, assembly of the RIP1-RIP3 necrosome was delayed, but not abolished in the absence of CYLD. In addition to the TNFR-1 complex, I found that RIP1 within the necrosome was also ubiquitinated. In the absence of CYLD, RIP1 ubiquitination in the NP-40 insoluble necrosome was greatly increased. Increased RIP1 ubiquitination correlated with impaired RIP1 and RIP3 phosphorylation, a signature of kinase activation. My results show that CYLD regulates RIP1 ubiquitination in the NP-40 insoluble necrosome, but not in the TNFR-1 signaling complex. Contrary to the current model, CYLD is not essential for necrosome assembly. Rather, it facilitates RIP1 and RIP3 activation within the necrosome and the corollary is enhancement of necrosome functionality and subsequent necrosis. My results therefore indicate that CYLD exerts its pro-necrotic function in the NP-40 insoluble necrosome, and illuminates the mechanism of necrosome activation.
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Moquin, David M. "Elucidating the Molecular Mechanism of CYLD-Mediated Necrosis: A Dissertation." eScholarship@UMMS, 2005. http://escholarship.umassmed.edu/gsbs_diss/659.
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TNFα-induced programmed necrosis is a caspase-independent cell death program that is contingent upon the formation of a multiprotein complex termed the necrosome. The association of two of the components of the necrosome, receptor interacting protein 1 (RIP1) and RIP3, is a critical and signature molecular event during necrosis. Within this complex, both RIP1 and RIP3 are phosphorylated which are consequential for transmission of the pro-necrotic signal. Namely, it has been demonstrated that RIP3 phosphorylation is required for binding to downstream substrates. Nevertheless, the regulatory mechanisms governing necrosome activation remain unclear. Since necrosis is implicated in a variety of different diseases, understanding the biochemical signaling pathway can potentially yield future drug targets. I was interested in identifying other regulators of necrosis in hope of gaining a better understanding of the necrosis signaling pathway and regulators of the necrosome. To address this, I screened a cancer gene siRNA library in a cell line sensitive to necrosis. From this, I independently identified CYLD as a positive regulator of necrosis. Previous studies suggest that deubiquitination of RIP1 in the TNF receptor (TNFR)-1 signaling complex is a prerequisite for transition of RIP1 into the cytosol and assembly of the RIP1-RIP3 necrosome. The deubiquitinase cylindromatosis (CYLD) is presumed to promote programmed necrosis by facilitating RIP1 deubiquitination in this membrane receptor complex. Surprisingly, I found that TNFα could induce RIP1-dependent necrosis in CYLD-/- cells. I show that CYLD does not regulate RIP1 ubiquitination at the receptor complex. Strikingly, assembly of the RIP1-RIP3 necrosome was delayed, but not abolished in the absence of CYLD. In addition to the TNFR-1 complex, I found that RIP1 within the necrosome was also ubiquitinated. In the absence of CYLD, RIP1 ubiquitination in the NP-40 insoluble necrosome was greatly increased. Increased RIP1 ubiquitination correlated with impaired RIP1 and RIP3 phosphorylation, a signature of kinase activation. My results show that CYLD regulates RIP1 ubiquitination in the NP-40 insoluble necrosome, but not in the TNFR-1 signaling complex. Contrary to the current model, CYLD is not essential for necrosome assembly. Rather, it facilitates RIP1 and RIP3 activation within the necrosome and the corollary is enhancement of necrosome functionality and subsequent necrosis. My results therefore indicate that CYLD exerts its pro-necrotic function in the NP-40 insoluble necrosome, and illuminates the mechanism of necrosome activation.
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Zingsheim, Morgan Robert. "Structure-Activity Study of a-N-Methylated SHU9119 Analogues, hMC4R/TNF-a Antagonists, and Mutational Studies of the Melanocyte Stimulating Hormone Receptor." Thesis, The University of Arizona, 2009. http://hdl.handle.net/10150/193426.
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The human melanocortin receptors (hMCRs) play a fundamental role in human behavior such as satiety, feeding, sexual and more. A set of SHU9119 peptide derivatives were studied for their structure-activity relationships. These peptides contained a sequential a-N-methylation amino acid scan.A second set of peptide derivatives intended to be used to create TNF-a; inhibition, via the melanocortin receptors. These peptides were shown to bind to all of the hMCR receptors, and only exhibit cAMP stimulation at hMC1R/hMC5R.The data from both of the sets of compounds illustrate that small changes in the stereochemistry of the SH9119 and TNF-a; derivatives cause drastic changes in the binding and the agonistic/antagonist properties of the compounds.This thesis determined the effect that hMC1R mutations have on the binding and cAMP response of well characterized ligands. This study ruled out 9 different residues for being the required for the cAMP response of the hMC1R.
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Glouchkova, Ludmila. "Biological role of the expression of tumor necrosis factor receptor ligand family molecules on acute leukemia cells." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=970363133.
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Rütten, Simon, Gerald F. Schusser, Getu Abraham, and Wieland Schrödl. "Release kinetics of tumor necrosis factor-α and interleukin-1 receptor antagonist in the equine whole blood." Universitätsbibliothek Leipzig, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-205268.
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Background: Horses are much predisposed and susceptible to excessive and acute inflammatory responses that cause the recruitment and stimulation of polymorphnuclear granulocytes (PMN) together with peripheral blood mononuclear cells (PBMC) and the release of cytokines. The aim of the study is to develop easy, quick, cheap and reproducible methods for measuring tumor necrosis factor alpha (TNF-α) and interleukin-1 receptor antagonist (IL-1Ra) in the equine whole blood cultures ex-vivo time- and concentration dependently. Results: Horse whole blood diluted to 10, 20 and 50 % was stimulated with lipopolysaccharide (LPS), PCPwL (a combination of phytohemagglutinin E, concanavalin A and pokeweed mitogen) or equine recombinant TNF-α (erTNF-α). TNF-α and IL-1Ra were analyzed in culture supernatants, which were collected at different time points using specific enzyme-linked immunosorbent assays (ELISA). Both cytokines could be detected optimal in stimulated 20 % whole blood cultures. TNF-α and IL-1Ra releases were time-dependent but the kinetic was different between them. PCPwL-induced TNF-α and IL-1Ra release was enhanced continuously over 24–48 h, respectively. Similarly, LPS-stimulated TNF-α was at maximum at time points between 8–12 h and started to decrease thereafter, whereas IL-1Ra peaked later between 12–24 h and rather continued to accumulate over 48 h. The equine recombinant TNF-α could induce also the IL-1Ra release. Conclusions: Our results demonstrate that similar to PCPwL, LPS stimulated TNF-α and IL-1Ra production time-dependently in whole blood cultures, suggesting the suitability of whole blood cultures to assess the release of a variety of cytokines in health and diseases of horse.
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Richter, Fabian [Verfasser], and Roland [Akademischer Betreuer] Kontermann. "Evolution of the antagonistic tumor necrosis factor receptor one-specific antibody ATROSAB / Fabian Richter ; Betreuer: Roland Kontermann." Stuttgart : Universitätsbibliothek der Universität Stuttgart, 2015. http://d-nb.info/113823480X/34.
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Patel, Brijesh. "The roles of tumour necrosis factor and its receptors in the injury, inflammation and resolution of acute lung injury." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/24695.
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The acute respiratory distress syndrome (ARDS) remains a major cause of morbidity and mortality in the intensive care. Despite improvements in intensive care and advances in respiratory support, mortality remains high with no active treatments. Tumour necrosis factor (TNF) is a cytokine that has been implicated in ARDS for over 30 years but its precise roles remain elusive. It signals through two main receptors - the p55 TNF receptor and p75 TNF receptor. The first aspect of this thesis investigated the roles of TNF receptors (TNFR) in the early phase of acute acid-induced lung injury. Using genetically modified mice we discovered that alveolar oedema, as a result of acid aspiration, was specifically mediated through the p55-TNFR, whereas, the p75-TNFR promoted a protective effect. Alveolar oedema formation occurred through an effect independent to the downstream inflammatory events, but instead through the activation of TNF/p55-TNFR/caspase-8 death signalling specifically in the alveolar epithelium. Furthermore, this death-signalling axis led to a reduced alveolar epithelial fluid clearance rate. Epithelial dysfunction occurred prior to epithelial cell death and pharmacological blockade of caspase-8 rescued epithelial function with improvements in gas exchange, suggesting that the activation of caspase-8 per se induced this functional deficit in the alveolar epithelium. The second part of the thesis describes the development of a longer-term model of acid aspiration aimed at extending investigation into the later, arguably more clinically relevant, phases of lung injury (0-10 days). Mice showed respiratory physiology that reached clinical ARDS criteria with significant inflammation and epithelial/endothelial injury, which importantly, resolved facilitating investigation into reparative processes. This model was further characterised using novel flow cytometry protocols to examine the compartmental location of leukocytes during the various phases of ARDS. This model provides a translational platform to allow investigation into the injurious, inflammatory, and resolution mechanisms of ARDS.
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Skuland, Trine. "Effects of Toll-like Receptor Agonists and Tumor Necrosis Factor-α in the SW982 Cell Model for Synovitis." Thesis, Norges teknisk-naturvitenskapelige universitet, Institutt for biologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-21416.
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Rheumatoid arthritis (RA) is a chronic, autoimmune joint disease characterized by a massive infiltration of immune cells and synovial lining hyperplasia. This ultimately leads to synovitis, i.e. inflammation of the synovial membrane, and excessive bone loss. Certain bone remodeling components are known to play a key role in the RA pathogenesis: receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), and dickkopf homolog 1 (DKK1). RANKL is a ligand essential to differentiation of the bone-degrading osteoclasts, while OPG can hinder this by competitive binding of RANKL. DKK1 inhibits activation of the bone-forming osteoblasts. In addition, toll-like receptors (TLRs) are believed to be central in RA. TLRs bind pathogen associated molecular patterns (PAMPs), but also damage associated molecular patterns (DAMPs) found on molecules present in inflamed joints. TLR ligand binding activates production of pro-inflammatory mediators.The exact events and pathways involved in RA are not fully understood. By using the synovial fibroblast (SF) cell line, SW982, as a model for synovitis, this master’s thesis aims to clarify certain signaling events. More specifically, the potential involvement of phospholipase A2 (PLA2) and cyclooxygenase (COX) in expression of bone remodeling genes, in response to TLR agonists and tumor necrosis factor (TNF)-α, was investigated. A known downstream effect of TLR activation is production of the pro-inflammatory cytokine TNF-α. Consequently, TNF-α’s effect on the TLR expression was also studied. Gene expression analysis, by quantitative polymerase chain reaction (qPCR), revealed that the SW982 cells express OPG and DKK1, and probably RANKL. In addition, the cells express TLR1-6, and possibly TLR7 too. It was shown, for the first time, that a TLR1/2 agonist (Pam3CSK4), a TLR2/6 agonist (FSL-1), and a TLR3 agonist (Poly(I:C)), increase the OPG and DKK1 gene expression in SW982 cells. The OPG mRNA increase was also detected at protein level by performing enzyme-linked immunosorbent assay (ELISA). Furthermore, activation of TLR1/2 and TLR2/6 was found to strongly induce IL-6 and COX-2 gene expression. It was discovered that cPLA2 and COX are involved in TLR1/2-mediated induction of DKK1, IL-6 and COX-2 gene expression, and possibly OPG expression. For the TLR2/6-mediated expression of these genes, the involvement of cPLA2 and COX is not as pronounced as for TLR1/2, but still likely. Altogether, these results indicate that the prostaglandin (PG) pathway is triggered upon TLR activation. Besides affecting the mentioned genes, this will lead to increased production of PGs. Prominent PG production is often observed in inflammatory conditions like RA. The activity of PLA2s in response to TLR agonists was studied by radioactivity assays. Activation of TLR1/2, TLR2/6 and TLR3 was found to increase the release of the inflammatory intermediate arachidonic acid (AA) – the first precursor of PG synthesis. Further assays suggested that the GIVA cPLA2 is the main PLA2 responsible for the increase in AA release, with possible involvement of Ca2+-independent PLA2 (iPLA2). Upon investigation of TNF-α’s effects, it was found that the SW982 cells increase their DKK1, TLR2 and TLR3 gene expression. The no-response results for RANKL, OPG, TLR1, and TLR4-7, and the no-response results regarding cPLA2’s involvement, were inconclusive due to non-optimal TNF-α stimulation. In conclusion, even though the bone-protective OPG is up-regulated by TLR activation, this activation may have more negative effects in the context of RA: DKK1, COX-2, IL-6 and AA release are increased, and these are all contributors of joint destruction in RA. In addition, OPG may also exert a negative effect. The protein can prevent apoptosis of SFs and thereby contribute to synovial hyperplasia. Because cPLA2 seems to be involved in the increase of the mentioned components, the enzyme may be an attractive target for reducing inflammatory responses set off by TLRs.
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Zhou, Wen. "Regulation of Tumor Necrosis Factor-Induced Cell Death and Toll-Like Receptor-Mediated Activation of Macrophages by SPATA2." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467202.
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Cell death and innate immunity are interconnected events for multicellular organisms to defend against pathogenic microbes and restrict tissue damage. Macrophages constitute an important population of innate immunity. Their survival and activation are critical for the local and systematic inflammation. Tumor necrosis factor (TNF) is an important pro-inflammatory factor and a major cause of cell death in vivo under pathological conditions. TNF can promote apoptosis, a hypoimmunogenic type of cell death that is preferentially triggered to restrict inflammation, or necroptosis, an immunogenic type of cell death that releases danger signals to the environment. These danger signals activate immune receptors such as toll-like receptors (TLRs). TLRs are the major family of receptors that sense extracellular pathogen- or damage-associated molecular patterns and elicit pro-inflammatory or antiviral responses.
Here I present a thesis describing the mechanism and functions of a gene named Spata2 that plays a dual role in regulating TNF-induced cell death as well as TLR-mediated pro-inflammatory responses. TNF-induced necroptosis involves a receptor-binding Complex I that initiates pro-survival signaling, and an intracellular Complex IIb that activates a toxic membrane-permeabilizing protein to execute cell death. I show that Spata2 promotes the formation of complex IIb without affecting the pro-survival function of complex I. In addition, I describe that Spata2 inhibits the production of pro-inflammatory cytokines, such as TNF, IL-6, and IL-12p40, in response to the activation of TLRs. Interestingly, Spata2 has no affect on the core signaling pathway that activates canonical NF-κB and MAP kinases; instead, it modulates IRAK2-mediated mRNA degradation upon TLR activation. Mutant mice that are deficient for Spata2 show enhanced susceptibility to TNF-induced septic shock, consistent with the immunosuppressive function of Spata2.Medical Sciences
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Richter, Christine. "Differential responsiveness of tumour necrosis factor receptors (TNFR) type 1 and 2 : the critical role of the TNFR stalk region." Thesis, University of Newcastle Upon Tyne, 2011. http://hdl.handle.net/10443/1284.
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The pro-inflammatory cytokine tumour necrosis factor (TNF) exerts its bioactivity via two plasma membrane receptors, TNF receptor (TNFR)1 and TNFR2. Both receptors are fully activated by membrane-bound TNF, while soluble TNF (sTNF) activates only TNFR1 efficiently. Preliminary data from our group suggest that the membrane proximal extracellular region (stalk region) and/or the transmembrane region of the TNFR control the differential responsiveness to sTNF. The aims of this project were to ascertain the region determining sTNF responsiveness and to investigate the underlying molecular mechanism(s). Fibroblasts from tnfr1-/-/tnfr2-/- double knockout mice were stably transfected with chimaeras consisting of the extracellular and transmembrane domain of TNFR and the intracellular portion of Fas (TNFR-Fas). Using this cellular system, I could show that 42 amino acids within the TNFR2 stalk region control responsiveness to sTNF. Replacement of the stalk regions of TNFR1-Fas and TNFR2-Fas with artificial linkers proved that stalk region length does not determine differential responsiveness. Furthermore, responsiveness to sTNF was not affected when either conserved proline residues or O-glycosylation sites in the TNFR2 stalk region were mutated. Moreover, partial replacement of the TNFR2 stalk region with overlapping artificial linkers also left sTNF responsiveness unaltered. Therefore, the underlying molecular mechanism controlling responsiveness to sTNF appears to be more complex and remains to be elucidated. Importantly, the critical role of the TNFR stalk region in sTNF responsiveness could also be confirmed for wild type TNFR2 at the level of signalling complex formation. Data from chemical crosslinking and confocal microscopy studies revealed that the stalk region controls ligand-independent receptor pre-assembly and formation of larger receptor clusters. Taken together, data obtained in this PhD thesis indicate that the TNFR2 stalk region is a major determinant of differential sTNF responsiveness and ligand-independent receptor-receptor interactions, the latter being a potential prerequisite for the formation of larger ligand/receptor clusters and signal initiation.
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Rousseau, Adrien. "Tumor necrosis factor Receptor-Associated Factor 4 (TRAF4) est une nouvelle protéine interagissant avec les phosphoinositides, impliquée dans la polarité et la migration cellulaire." Thesis, Strasbourg, 2013. http://www.theses.fr/2013STRAJ108/document.
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TRAF4 est un gène fréquemment surexprimé dans les carcinomes suggérant qu’il y joue un rôle. Tandis que la protéine TRAF4 est majoritairement localisée dans les jonctions serrées (JS) des cellules épithéliales mammaires (CEM) normales, elle s’accumule dans le cytoplasme des CEM malignes. Dans cette étude, nous montrons que TRAF4 possède un nouveau domaine liant les phosphoinositides (PIP) et que ce dernier est requis pour son recrutement aux JS. Des analyses moléculaires et structurales ont montré que le domaine TRAF de TRAF4 forme un trimère pouvant lier jusqu’à trois molécules de lipides grâce à des résidus basiques présents à la surface. Des études cellulaires indiquent que TRAF4 régule négativement les JS et augmente la migration cellulaire. Ces deux fonctions sont dépendantes de sa capacité à lier les PIPs. Notre travail suggère que la surexpression de TRAF4 pourrait contribuer à la progression des cancers du sein en déstabilisant les JS et en favorisant la migration cellulaireTRAF4 (tumor necrosis factor (TNF) receptor-associated factor 4) is frequently overexpressed in carcinomas suggesting a specific role in cancer. While TRAF4 protein is predominantly found at tight junctions (TJ) in normal mammary epithelial cells (MEC), it accumulates in the cytoplasm of malignant MEC. How TRAF4 is recruited and functions at TJ is unclear. Here we show that TRAF4 possesses a novel phosphoinositide (PIP)- binding domain crucial for its recruitment to TJ. Molecular and structural analyses revealed that the TRAF domain of TRAF4 exists as a trimer which binds up to 3 lipids using basic residues exposed at its surface. Cellular studies indicated that TRAF4 acts a negative regulator of TJ and increases cell migration. These functions are dependent from its ability to interact with PIPs. Our results suggest that TRAF4 overexpression might contribute to breast cancer progression by destabilizing TJ and favoring cell migration
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Halford, Emily Elisabeth. "The role of group 3 innate lymphoid cells and tumour necrosis factor receptors in the survival and function of regulatory T cells." Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6679/.
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The ability to therapeutically manipulate regulatory T (Treg) cell survival/function would have far reaching implications; with the potential to limit immune pathology in autoimmune disease, allergy and transplantation; and to reduce regulation of anti-tumour responses in cancer. This study has established a method to study the survival and function of antigen specific Treg cells in vivo, adapting an existing approach in which an endogenous naïve T cell population is expanded and tracked. Multiple immunisation of antigen, and an agonistic anti-DR3 antibody were used to ensure a sufficient number and proportion of Treg cells could be expanded. Further to this, an assay for investigating Treg cell function in vivo was applied to this system. This approach revealed that the tumour necrosis factor receptors OX40 and CD30 may play a role in Treg function, as well as expansion. Unexpectedly, these data also revealed that in the absence of OX40 there is a gross defect in the function of CD4 T cells. A regulatory role of group 3 Innate Lymphoid cells is emerging in the literature, and in accordance with this, this study demonstrates that Treg cell expansion is grossly impaired in mice which lack RORγt, their lineage defining transcription factor.
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Romanatto, Talita. "O Knockout para o receptor 1 de TNF-a protege contra obesidade induzida por dieta." [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310352.
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Orientador: Licio Augusto VellosoTese (doutorado) - Universidade Estadual de Campinas. Faculdade de Ciencias Medicas
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Resumo: O aumento da prevalência de obesidade em várias regiões do planeta é um dos mais importantes fenômenos clínico-epidemiológicos da atualidade. Fatores como a mudança do hábito alimentar e o estilo de vida sedentário, aliados a determinantes genéticos ainda pouco conhecidos desempenham um papel relevante na patogênese dessa doença. Nos últimos quinze anos, desde o descobrimento do hormônio leptina, avanços consideráveis foram obtidos na caracterização dos mecanismos hipotalâmicos do controle da ingestão alimentar e da termogênese. Em um estudo recente demonstrou-se que o consumo de uma dieta rica, em gordura induz a expressão de várias citocinas pró-inflamatórias no hipotálamo e que a inibição da via de sinalização intracelular da serina quinase JNK é capaz de reverter parcialmente algumas das conseqüências clínicas do consumo dessa dieta (De Souza et al, 2005). No presente estudo avaliou-se a importância do receptor 1 de TNF-cc(TNFRI) na gênese do processo inflamatório desencadeado pela dieta rica em gordura. O TNFR1 é responsável pela maioria dos efeitos do TNF-ct, no entanto no contexto da obesidade induzida por dieta, a função desse receptor não está completamente esclarecida. Para tanto, camundongos knockout (KO) para o TNFR1 e seu respectivo background genético, C57BL6, foram tratados por 8 semanas com dieta hiperlipídica e observamos que o TNFR1 KO está protegido da obesidade induzida por dieta por meio de aumento na termogênese. Em ambas as dietas, padrão e hiperlipídica (HF), TNFR1 KO ganha menos peso apesar de aumento na ingestão alimentar. Adiposidade e diâmetro dos adipócitos estão reduzidos, assim como as concentrações sanguíneas de insulina e leptina. TNFR1 KO estão protegidos de resistência hipotalâmica à via da leptina por meio de preservação da sinalização da leptina através de JAK2, STAT3 e FOX01. TNFR1 KO apresentam aumento de termogênese, pelo aumento do consumo de 02, aumento da expressão de UCP-1 e UCP-3, no tecido adiposo marrom e músculo esquelético, respectivamente, e aumento do consumo de O2 de mitocôndrias isoladas de músculo. Isso demonstra que a via de sinalização do TNF-a pelo TNFR1 representa um importante mecanismo envolvido na termogênese deficiente associada à obesidade.
Abstract: In diet-induced obesity, hypothalamic and systemic inflammatory factors trigger intracellular mechanisms that lead to resistance to the main adipostatic hormones, leptin and insulin. Tumor necrosis factor-alpha (TNF-a) is one of the main inflammatory factors produced during this process and its mechanistic role as an inducer of leptin and insulin resistance has been widely investigated. Most of TNF-a inflammatory signals are delivered by TNFR1; however, the role played by this receptor in the context of obesity-associated inflammation is not completely known. Here, we show that TNFR1 knockout (TNFR1 KO) mice are protected from diet-induced obesity due to increased thermogenesis. Under standard rodent chow or ligh-fat diet, TNFR1 KO gain significantly less body mass in spite of increased caloric intake. Visceral adiposity and mean adipocyte diameter are reduced and Dlood concentrations of insulin and leptin are lower. Protection from hypothalamic eptin resistance is evidenced by increased leptin-induced suppression of food ntake and preserved activation of leptin signal transduction through JAK2, STAT3 jnd FOX01. Under high fat diet, TNFR1 KO mice present a significantly increased expression of the thermogenesis-related neurotransmitter, TRH. Further evidence if increased thermogenesis includes the increased 02 consumption and C02 traduction in respirometry measurements, increased expressions of UCP1 and JCP3 in brown adipose tissue and skeletal muscle, respectively, and increased 02 onsumption by isolated skeletal muscle fiber mitochondria. This demonstrates that 'NF-ct signaling through TNFR1 is an important mechanism involved in obesity-ssociated defective thermogenesis.
Doutorado
Medicina Experimental
Doutor em Fisiopatologia Medica
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Berkhout, Laura Katharina [Verfasser], and Gisa [Akademischer Betreuer] Tiegs. "Role of Tumor necrosis factor receptor 1 in a mouse model of chronic liver inflammation / Laura Katharina Berkhout ; Betreuer: Gisa Tiegs." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2020. http://d-nb.info/1214370373/34.
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Miller, Katherine. "Genetic susceptibility in Alzheimer's Disease and the role of lipid metabolism." Connect to text online, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1164830757.
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Thesis (Ph. D.)--Case Western Reserve University, 2006.[School of Medicine] Department of Epidemiology and Biostatistics. Includes bibliographical references. Available online via OhioLINK's ETD Center.
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Heigl, Ulrike [Verfasser], and Wulf [Akademischer Betreuer] Schneider. "Impact of tumor necrosis factor receptor-1 signalling to Listeria monocytogenes-containing phagosomes and its role for bacterial eradication / Ulrike Heigl. Betreuer: Wulf Schneider." Regensburg : Universitätsbibliothek Regensburg, 2011. http://d-nb.info/1030177740/34.
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Karathanasis, Christos [Verfasser], Mike [Akademischer Betreuer] Heilemann, Mike [Gutachter] Heilemann, and Gerhard [Gutachter] Hummer. "Quantitative photoactivated localization microscopy reveals the oligomeric state of the tumor necrosis factor receptor 1 / Christos Karathanasis ; Gutachter: Mike Heilemann, Gerhard Hummer ; Betreuer: Mike Heilemann." Frankfurt am Main : Universitätsbibliothek Johann Christian Senckenberg, 2019. http://d-nb.info/1202297951/34.
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Galdino, Júnior Hélio. "Produção de fator de necrose tumoral (TNF) em hemoculturas humanas induzida por agonistas de TLR2 (toll-like receptor 2): modulação pelo fator ativador de plaquetas (PAF)." Universidade Federal de Goiás, 2008. http://repositorio.bc.ufg.br/tede/handle/tede/5424.
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Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq
Microorganisms express conserved molecules which ones activate the innate immune system. These molecules are known as pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) and bacterial lipoproteins. The PAMPs can be recognized by Toll-like receptors (TLR). The innate immunity activation through TLR pathway induces pro-inflammatory cytokines and lipid mediators, as tumor necrosis factor (TNF) and platelet-activating factor (PAF), respectively. Several reports showed the interaction between TLR4 and PAF receptor (PAFR) signaling to the TNF production; however, the interaction between PAF and other TLR was poorly investigated. The aim of this study was to evaluate the PAF regulatory activity on TLR2-induced TNF production. Thus, Mycoplasma fermentans PG 18 lipoproteins (LAMPf), TLR2/TLR6 agonists and Pam3Cys, a synthetic lipopeptide agonist of TLR2/TLR1 were added to human whole blood cultures and TNF was evaluated by enzyme-linked immunosorbent assay. To evaluate the effects of endogenous PAF on TNF production, a PAF receptor antagonist, WEB2170 was used, and to evaluate the effect of exogenous PAF, PAF was added to the cultures. The blood cultures were also activated with Gram-positive or negative heat-killed bacteria (Staphylococcus aureus or Escherichia coli). The TLR2 expression on polymorphonuclear (PMN) and monocytes were evaluated by flow cytometry, analyzing total cellularity for PMN and CD14+ cells for monocytes. LAMPf, Pam3Cys or LPS induced TNF and the treatment with WEB2170 increased TNF production after TLR2 activation, but not after TLR4 activation. Priming of the blood cultures with PAF up regulated TLR2- induced TNF production. Addition of PAF did not alter TNF release induced by LPS. E. coli induced higher levels of TNF than S. aureus and the treatment with WEB2170 lead to a significant reduction of S. aureus-induced TNF release. However, addition of PAF did not significantly alter bacteria-induced TNF production. With E. coli neither treatment with WEB2170 nor with PAF modulated TNF release. Results indicate that PAF can increase or decrease TNF production induced by TLR2 depending on the time when PAF is combined with TLR2. The increase of the TNF production after extended priming with PAF it was not caused by an increase in TLR2 expression. Thus, it is suggested that interaction between PAFR and TLR2 signaling determines the levels of TNF release. TLR2/PAF/TNF signaling pathway can be relevant in innate immune responses against Gram positive bacteria as well as in inflammatory diseases.
Os microrganismos expressam moléculas conservadas que ativam as células do sistema imune inato. Estas são conhecidas como padrões moleculares associados aos patógenos (PAMPs), tais como o lipopolissacarídeo (LPS) e as lipoproteínas bacterianas. Estes PAMPs são reconhecidos por receptores da família dos Toll-like receptors (TLR). A ativação das células da imunidade natural via TLR induz a produção de citocinas e mediadores lipídicos pro-inflamatórios dentre eles, o fator de necrose tumoral (TNF) e o fator ativador de plaquetas (PAF), respectivamente. A modulação da produção de TNF induzida por agonista de TLR4 (o LPS), pelo PAF, é conhecida, no entanto, a interação entre PAF e outros TLR foi pouco investigada. O presente trabalho teve o objetivo de avaliar a atividade moduladora do PAF na produção de TNF induzida por agonistas de TLR2. Para isto, foram utilizados as lipoproteínas de Mycoplasma fermentans PG 18 (LAMPf), agonistas de TLR2/TLR6 e o Pam3Cys, um lipopeptídeo sintético agonista de TLR2/TLR1. Culturas de sangue total periférico humano foram ativadas com os agonistas de TLR2 ou TLR4 e o TNF foi avaliado nos sobrenadantes, por meio do ELISA. Para avaliar os efeitos do PAF endógeno na produção do TNF, foi utilizado o antagonista do receptor do PAF (PAFR), o WEB2170, e para avaliar o efeito do PAF exógeno, o PAF foi adicionado às hemoculturas. As hemoculturas também foram ativadas com bactérias inteiras (S. aureus ou E. coli) inativadas pelo calor. A expressão de TLR2 em polimorfonucleares (PMN) e monócitos foi avaliada por citometria de fluxo, analisando a celularidade total para os PMN e as células CD14+, para os monócitos. As LAMPf, Pam3Cys ou LPS induziram TNF nas hemoculturas. O tratamento com WEB2170 aumentou a produção de TNF nas hemoculturas estimuladas com agonistas de TLR2, mas não de TLR4. A pré-estimulação das hemoculturas com o PAF aumentou a produção de TNF induzida pelos agonistas de TLR2. A adição de PAF não causou alterações significantes na produção de TNF induzida pelo LPS. Nos ensaios com as bactérias inteiras, E. coli induziu maiores concentrações de TNF do que S. aureus. O tratamento com WEB2170 das hemoculturas estimuladas com S. aureus reduziu a produção de TNF, no entanto, a adição de PAF não alterou significantemente a produção de TNF nas hemoculturas estimuladas com as bactérias. Para E. coli, nem o tratamento com WEB2170, nem com o PAF alterou significantemente a produção de TNF. Os resultados indicam que o PAF pode aumentar ou diminuir a produção de TNF induzida por agonista de TLR2, dependendo do momento em que ele ativa o PAFR em relação à ativação do TLR2. O aumento da produção de TNF após prolongada pré-ativação das hemoculturas com o PAF não foi devido a um aumento na expressão de TLR2. Assim, é sugerido que a interação entre as vias bioquímicas de sinalização do PAFR e do TLR2 determina o nível de produção de TNF. A via de sinalização TLR2/PAF/TNF pode ser importante na imunidade inata contra infecções causadas por bactérias Gram positivas tão bem quanto em doenças inflamatórias.
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Dinnetz, Joyce Marie. "Omega-3 fatty acid supplementation reduces basal TNFalpha but not toll-like receptor stimulated TNFalpha in full sized and miniature mares." Thesis, Manhattan, Kan. : Kansas State University, 2009. http://hdl.handle.net/2097/1497.
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Thangarajh, Mathula. "B-cell-survival factors in multiple sclerosis and myasthenia gravis /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-097-8/.
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Zhou, Xueyuan. "Follicular Dendritic Cells, Human Immunodeficency Virus Type 1, and Alpha 1 Antitrypsin." BYU ScholarsArchive, 2012. https://scholarsarchive.byu.edu/etd/3407.
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HIV/AIDS is raging and causing millions of deaths around the world. The major challenge in treating HIV/AIDS is the establishment of HIV reservoirs where the viruse escapes both drug and immune system attempts at eradication. Throughout the course of HIV/AIDS, productive HIV infection occurs primarily in the lymphoid follicles or germinal centers (GC) surrounding follicular dendritic cells (FDC). In the GCs, FDCs trap and maintain infectious HIV for years and provide these infectious viruses to the host cells. FDCs also attract B and T cells into the GCs and increase the ability of CD4+ T cells to be infected. Additionally, FDCs also mediate the increase of HIV replication in HIV-infected CD4+ T cells. Recently, several clinical cases and in vitro studies suggest that alpha-1-antitrypsin (AAT) might inhibit HIV infection and replication. Therefore, I hypothesized that AAT inhibited both the infection and replication of HIV in primary CD4+ T cells. I also postulated that AAT inhibited the FDC-mediated contributions that potentiate HIV infection and replication. To test whether AAT inhibited HIV infection in lymphocytes, CD4+ T cells were pretreated with AAT and then incubated with HIV to detect HIV infection. To exam whether AAT inhibited HIV replication, infected CD4+ T cells were cultured with AAT to detect the replication of HIV. To determine whether AAT blocked the FDC-mediated contributions to HIV pathogenesis, activated or resting FDCs were treated with AAT to detect the trapping and maintenance of HIV. The results suggested that AAT inhibited HIV entry into CD4+ T cells by directly interacting with gp41 and thereby inhibiting the interaction between HIV and CD4+ T cells. AAT also inhibited HIV replication in infected CD4+ T cells. Further study revealed that AAT interacted with low-density lipoprotein-receptor related protein to mediate the internalization of AAT through a clathrin-dependent endocytic process in CD4+ T cells. Subsequently, internalized AAT was transported from the endosome to the lysosome and then released into the cytosol. In the cytosol, AAT directly interacted with IκBα to block its polyubiquitinylation at lysine residue 48, which resulted in the accumulation of phosphorylated/ubiqutinylated IκBα in the cytosol. In turn, the dissociation of IκBα from NF-κB was blocked, which thereby inhibited the nuclear translocation and activation of NF-κB. Additionally, AAT also down-regulated FDC-CD32 and FDC-CD21 expression, which are regulated by NF-kB, thereby inhibiting the trapping and maintenance of HIV on FDCs. Hence, AAT not only suppresses HIV replication, but also blocks HIV replication in CD4+ T cells. Moreover, AAT also inhibits the activation of FDCs thereby affecting the trapping and maintenance of HIV.
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Bradburn, Jennifer Elizabeth. "Reactive species promotion of head and neck squamous cell carcinoma." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1166555968.
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Hossain, Akter. "Studies on Redox-proteins and Cytokines in inflammation and Cancer." Doctoral thesis, Linköping : Univ, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-8798.
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