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Oates, Anna. "Mapping of functional TNFα-ligand interactions." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.615706.
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Orsini, Marion. "Inhibition de l’érythropoïèse par la voie TNFα/sphingomyélinase/céramide : rôle du réseau de régulation microARN/facteurs de transcription et impact sur l’autophagie." Thesis, Université de Lorraine, 2017. http://www.theses.fr/2017LORR0225/document.
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L’anémie est un symptôme fréquent chez les patients atteints de cancer. La libération de la cytokine pro-inflammatoire TNFα, un inhibiteur connu de l’érythropoïèse, en est l’une des causes. L’érythropoïèse est un processus nécessitant l’arrêt de la prolifération et l’autophagie. Les résultats précédents ont montré que le TNFα inhibe l’expression des marqueurs érythroïdes et module l’expression de facteurs de transcription (FT) hématopoïétiques. Notre objectif est d’étudier l’implication de la voie TNFα/sphingomyélinase (SMase)/céramide dans l’inhibition de l’érythropoïèse en utilisant des cellules souches hématopoïétiques CD34+ induites à se différencier par l’érythropoïétine recombinante (Epo). Par l’utilisation de céramides exogènes, de SMase bactérienne et d’inhibiteurs de SMases, nous montrons l’implication de la voie SMase/céramide dans l’inhibition de l’expression des marqueurs érythroïdes mais également dans l’induction de la différenciation myéloïde avec une augmentation de l’expression du CD11b. Cet effet sur la différenciation est corrélé à la modulation du réseau FT/miR impliquant GATA-1, GATA-2 et PU.1 et les miR-144, 451, 155, 146a et 223. De plus, l’analyse par microscopie électronique à transmission, l’absence de formation de punctae GFP-LC3 et l’accumulation de SQSTM1/p62 montrent que le TNFα et les céramides inhibent l’autophagie induite par l’Epo. L’analyse des protéines impliquées dans la régulation de l’autophagie montre que le TNFα et les céramides activent mTOR. Son implication est confirmée par l’utilisation de rapamycine et l’inhibition de ULK1 et Atg13. De plus, le TNFα et les céramides inhibent l’expression de bécline 1 et de la formation du complexe Atg5-Atg12. Ces résultats démontrent que la voie TNFα/SMase/céramide joue un rôle dans l’homéostasie hématopoïétique par l’inhibition de l’érythropoïèse au profit de la myélopoïèse, en impactant les réseaux de régulation FT/miR et le processus d’autophagieAnemia is a common symptom in cancer patients. It can be caused by the release of pro-inflammatory cytokines such as TNFα, a known inhibitor of erythropoiesis. Erythropoiesis involves proliferation arrest and autophagy. Our previous studies showed that TNFα inhibits the expression of erythroid markers as well as hematopoietic transcription factors (TF) expression. The aim is to study the involvement of TNFα/sphingomyelinase (SMase)/ceramide pathway in erythropoiesis inhibition using recombinant erythropoietin (Epo)-induced CD34+ hematopoietic stem cells. Using exogenous ceramides, a bacterial SMase and sphingomyelinase inhibitors, we show the involvement of SMase/ceramide pathway in the inhibition of erythroid markers as well as the induction of myeloid differentiation as shown by the increase in CD11b expression. This effect is correlated to the modulation of the TF/miR network involving GATA-1, GATA-2 and PU.1 as well as miR-144, 451, 155, 146a and 223. We show that TNFα and ceramides inhibit Epo-induced autophagy through transmission electron microscopy analysis, the absence of GFP-LC3 punctae formation and SQSTM1/p62 accumulation. Analysis of proteins involved in autophagy regulation showed that TNFα and ceramides activate mTOR, which is confirmed using rapamycin as well as the inhibition of ULK1 and Atg13. Moreover, TNFα and ceramides inhibit Beclin 1 expression and Atg5-Atg12 complex formation. These results demonstrate the role of TNFα/SMase/ceramide pathway in hematopoietic homeostasis through an erythropoiesis-myelopoiesis switch resulting from perturbation of TF/miR network and autophagy
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Mouhsine, Hadley. "Développement de nouveaux inhibiteurs du TNFα identifiés par Drug Design." Thesis, Paris, CNAM, 2012. http://www.theses.fr/2012CNAM0842/document.
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Les anticorps monoclonaux ont constitué une révolution dans le traitement desmaladies inflammatoires chroniques, mais ils présentent des inconvénients majeurs (effetssecondaires, coûts élevés, résistances).Notre équipe développe des inhibiteurs du TNFα par deux approches : immunisationactive contre des peptides de cytokine pour générer des anticorps neutralisants et petitesmolécules chimiques pouvant inhiber directement le TNFα.J’ai évalué in vitro les meilleurs composés d’un criblage de chimiothèque in silico, etnotamment identifié une petite molécule qui a protégé les animaux dans deux modèles demaladies in vivo (choc septique et colite au DSS). J’ai aussi réalisé l’analyse d’analogueschimiques des meilleurs composés identifiés in vitro.J’ai également évalué l’immunogénicité de plusieurs peptides de TNFα mais lesanticorps générés n’étaient pas neutralisants in vitro et nous n’avons donc pas testé lespeptides in vivo.Mon travail s’est situé à l’interface de la bioinformatique, de la chimie, et de labiologie et m’a permis de bien comprendre les enjeux du développement moderne dumédicamentMonoclonal antibodies have been a revolution for the treatment of chronicinflammatory diseases but present several drawbacks (secondary effects, prohibitive costs,resistance)Our team develops TNFα inhibitors using two approaches : active immunizationagainst cytokine peptides and small compounds having a direct inhibition on TNFα.I have evaluated in vitro the best compounds selected after in silico screening of achemical library and I have identified a small molecule which was protective in two animalmodels (septic shock and DSS induced colitis). I have also analyzed chemical analogues ofthe best compounds found in vitro.I have also tested the immunogenicity of TNFα peptides but they did not yieldneutralizing antibodies in vitro, and we thus did not test them in vivo.My work was at the interface of bioinformatics, chemistry and biology, and this hasenabled me to understand the key issues in the modern development of drugs
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Fouche, Celeste. "Differential effects of TNfα on satellite cell differentiation." Thesis, Stellenbosch : Stellenbosch University, 2007. http://hdl.handle.net/10019.1/19596.
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Thesis (MSc)--University of Stellenbosch, 2007.ENGLISH ABSTRACT: Tumour necrosis factor alpha (TNFα) is a pleiotropic cytokine and has a wide variety of dose dependent cellular effects ranging from cell growth and differentiation, to inducing apoptosis. It has long been implicated in muscle and non-muscle inflammatory disorders, such as muscle wasting in chronic disease states, and rheumatoid arthritis. However, a physiological role for TNFα in muscle regeneration has been proposed as elevated levels of the cytokine are present when muscle regeneration processes are initiated: TNFα is secreted by infiltrating inflammatory cells, and by injured muscle fibres. Adult skeletal muscle contains a population of resident stem cell-like cells called satellite cells, which become activated, proliferate and differentiate following muscle injury to bring about repair of damaged muscle. Much research on the effects of TNFα on satellite cell differentiation has been conducted in recent years. It is however difficult to get a complete characterisation of the cytokine’s action as all models used slightly differ. We aimed therefore at providing comprehensive assessment of the effects of increasing doses of chronically supplemented TNFα on differentiating C2C12 cells. Cells were allowed to differentiate with or without TNFα supplementation for 7 days. Differentiation was induced at day 0. The effect on differentiation was assessed at days 1, 3, 5, and 7 by western blot analysis, and supplementary immunohistochemical analysis at days 1, 4, and 7 of markers of differentiation - muscle regulatory factors: MyoD and myogenin, markers of the cell cycle p21, PCNA, and the integral signalling molecule, p38MAPK. TNFα supplementation at day 1 tended to positively regulate early markers of differentiation. With continued supplementation however, markers of differentiation decreased dose dependently in treated cultures as the initial effect appeared to be reversed: A trend towards a dose dependent decrease in MyoD, myogenin and p21 protein existed in treated cultures at days 3, 5, and 7. These findings were significant at day 5 (p21, p<0.05), and day 7 (myogenin, p<0.05). A significant dose dependent decrease in p38 phosphorylation was evident at day 3 (p<0.05), while phospho-p38 was dose dependently increased at day 7 (p<0.05). Taken together, these data show that TNFα supplementation for 24 hours following the induction of differentiation in vitro, tends to increase levels of early markers of differentiation, and with continued TNFα supplementation decrease markers of differentiation in a dose dependent fashion. This study provides a comprehensive characterisation of the dose and time dependent effects of TNFα on satellite cell differentiaton in vitro. The model system used in the current study, allows us to make conclusions on more chronic disease states.
AFRIKAANSE OPSOMMING: Tumor nekrose faktor alfa (TNFα) is ‘n pleiotropiese sitokien wat ‘n wye verskeidenheid, dosis afhanklike, sellulêre effekte te weeg bring. Hierdie sellulêre effekte sluit sel groei en differensiasie tot sel dood in. TNFα is by beide spier en niespier inflammatoriese stoornisse soos spier tering in kroniese siektetoestande, en rumatiese artritis betrek. ‘n Fisiologiese rol vir TNFα is egter voorgestel aangesien verhoogde vlakke van die sitokien tydens inisiasie van spier herstel meganismes teenwoordig is: TNFα word deur infiltrerende inflammatoriese selle, asook deur beseerde spier vesels afgeskei. Volwasse skeletspier bevat ‘n populasie stamselagtige selle, sogenoemde satelliet selle. Laasgenoemde word geaktiveer, prolifereer en differensieër volgende spierbesering, om sodoende herstel van beskadigde spier te weeg te bring. Baie navorsing op die effekte van TNFα op satelliet sel differensiasie is onlangs uitgevoer. Dit is egter aansienlik moeilik om volgens hierdie navorsing‘n algehele beeld van TNFα se aksies te vorm aangesien alle modelle wat gebruik word verskil. Ons doel was daarom om ‘n omvangryke assessering van toenemende konsentrasies kronies gesupplementeerde TNFα op differensieërende C2C12 selle op ‘n enkele model uit te voer. Selle was vir 7 dae met of sonder TNFα supplementasie gedifferentieër. Differensiasie was by Dag 0 geïnduseer. TNFα se effek op differensiasie is op dae 1, 3, 5, en 7 deur middel van western blot analise geassesseer. Aanvullende immunohistochemiese bepalings op dae 1, 4, en 7 is verder deurgevoer. Merkers vir differensiasie het die spier regulatoriese faktore MyoD en miogenien, sel siklus merkers p21 en PCNA, asook die integrale sein transduksie molekule p38MAPK ingesluit. TNFα supplementasie by dag 1 het geneig om vroeë merkers van differensiasie positief te reguleer. Met voortdurende supplementasie is die vroeë positiewe effekte (op ‘n dosis afhanklike manier) egter omgekeer: ‘n neiging teenoor (‘n dosis afhanklike) vermindering in MyoD, miogenien en p21 proteïen het in behandelde kulture op dae 3, 5, en 7 bestaan. Hierdie bevindinge was beduidend by dag 5 (p21, p<0.05), en dag 7 (miogenien, p<0.05). A beduidende dosis afhanklike afname in p38 fosforilasie was duidelik by dag 3 (p<0.05), terwyl fosfo-p38 by dag 7 verhoog het met verhoogde konsentrasie TNFα (p<0.05). Bogenoemde saamgevat, dui aan dat TNFα supplementasie 24h volgende die induksie van differensiasie in vitro, verhoogde vlakke van vroeë differnsiasie merkers te weeg bring. Met voortdurende TNFα supplementasie, word differensiasie merkers egter met toenemende dosis verminder. Hierdie studie voorsien ‘n omvattende karakterisering van die dosis- en tyd afhanklike effekte van TNFα op satelliet sel differesiasie in vitro. Die model sisteem in hierdie studie gebruik, maak afleidings oor meer kroniese siektetoestande moontlik.
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Zeiller, Caroline. "Phospholipase D, perméabilité endothéliale, et apoptose TNFα dépendante." Lyon, INSA, 2007. http://theses.insa-lyon.fr/publication/2007ISAL0087/these.pdf.
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La phospholipase D (PLD) est une enzyme membranaire qui intervient au cœur du métabolisme lipidique en générant un second messager, l’acide phosphatidique (PA) impliqué dans de nombreuses fonctions cellulaires. Deux isoformes PLD1 et PLD2 contribuent à sa synthèse chez les mammifères. Nous avons montré que la PLD augmente la perméabilité de monocouches de cellules endothéliales (lignée HUV-EC-C) aux macromolécules en permettant un remodelage du cytosquelette d’actine. L’isoforme PLD2 jouerait un rôle prépondérant via sa localisation au sein des cavéoles membranaires. Nous avons étudié le rôle de la PLD dans l’apoptose des cellules ECV304 induite par le TNFα, une cytokine activant à la fois des voies de survie et des voies pro-apoptotiques. Nous avons aussi étudié le rôle de la PLD dans l’apoptose des cellules ECV304 induite par le TNFα une cytokine activant à la fois des voies de survie et des voies pro-apoptotiques. Nous avons montré que la PLD a un rôle protecteur contre la mort cellulaire induite par TNFα en présence de cycloheximide, l’isoforme PLD1 étant plus spécifiquement mise en jeu. Divers mécanismes expliquant cet effet protecteur sont proposésPLD is a membrane-bound enzyme which plays a key role in lipid metabolism by generating phosphatidic acid, an anionic phospholipid involved in many cellular functions. Two isoforms PLD 1 and PLD2 exist in mammals. We have shown that PLD enhances the permeability of endothelial cell monolayers (HUV-EC-C cells) through an actin reorganization which is characterized by synthesis of stress fibers. PLD2 might be more particularly implicated, because of its sub cellular localization to membrane caveolae. We also studied the role of PLD in Tumor Necrosis Factor alpha (TNFα)-induced apoptosis of ECV304 cells. TNFα, a pleiotropic cytokine, activates both apoptotic and pro-survival signals depending on the cell model. We showed that PLD exerts a protective effect against cell death induced by TNFα in the presence of an inhibitor of protein synthesis, cycloheximide. PLD 1 isoform plays a predominant role in this process. Different mechanisms explaining the protective role of PLD are proposed
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Fischer, Johannes. "Tierexperimentelle Untersuchungen zu Stress, Zytokinen und depressionsähnlichem Verhalten." Doctoral thesis, Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-169143.
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Die vorliegende publikationsbasierte Dissertationsschrift erörtert auf der Basis experimenteller Untersuchungen im Tiermodell die Auswirkungen von Stress auf die Zytokinproduktion und depressionsähnliches Verhalten. Außerdem wird getestet, ob die Blockade des Zytokins Tumornekrosefaktor-α (TNF‑α) eine Möglichkeit zur antidepressiven Intervention darstellt.
Einleitend werden die Zusammenhänge von Stress, Zytokinen und Depression referiert sowie das hypothetische Modell erläutert, das den publizierten Untersuchungen zugrunde liegt. Es wird hypothetisiert, dass Stress zur Erhöhung der Produktion proinflammatorischer Zytokine führt und dass die vermehrte Zytokinproduktion depressive Verhaltensweisen hervorruft. Aus dieser Annahme leitet sich die Möglichkeit ab, durch Blockade der Wirkung des proinflammatorischen Zytokins TNF‑α antidepressive Effekte zu erzielen.
In den beiden Arbeiten „The impact of social isolation on immunological parameters in rats“ (Archives of Toxicology) und „Stress-induced cytokine changes in rats“ (European Cytokine Network) wurde der Einfluss von sozialer Isolation, chronischem, milden und akutem Stress auf die Zytokinproduktion untersucht. In diesen Untersuchungen führten die verschiedenen Stressarten zu einer Modulation der Produktion proinflammatorischer Zytokine.
Die dritte Publikation „Antidepressant effects of TNF‑α blockade in an animal model of depression“ (Journal of Psychiatric Research) berichtet von einem Experiment, in dem untersucht wurde, ob der TNF‑α-Inhibitor Etanercept antidepressive Effekte aufweist. Tatsächlich zeigte sich unter Etanercept ein Rückgang des depressionsähnlichen Verhaltens im forced swim test (FST) analog zu Verhaltensänderungen durch das in Tierversuchen als Standard-Antidepressivum geltende Imipramin.
Die Autoren schlussfolgern, dass das Zytokinsystem durch Stress moduliert wird und so in die pathophysiologische Entwicklung einer Depression involviert sein könnte. Zytokininhibitoren könnten eine neue Klasse der Antidepressiva bei Therapieresistenz werden, wenn sich die Ergebnisse dieser Tierversuche in Studien an Probanden und an Patienten replizieren lassen.
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Faletti, Laura [Verfasser], and Christoph [Akademischer Betreuer] Borner. "Molecular mechanisms of TNFα sensitization to fasL-induced apoptosis." Freiburg : Universität, 2017. http://d-nb.info/1183569556/34.
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Marshall, Aiden Christopher James 1976. "The role of Fas and TNFα in experimental autoimmune gastritis." Monash University, Dept. of Pathology and Immunology, 2003. http://arrow.monash.edu.au/hdl/1959.1/9413.
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Somers, Sarin J. "Role of nuclear factors kappa-B in TNFα-induced cytoprotection." Master's thesis, University of Cape Town, 2006. http://hdl.handle.net/11427/3466.
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SAITO, Kiyoshi, Jun YOSHIDA, Hisao SEO, Kenichi WAKABAYASHI, Fukushi KAMBE, Takashi NAGAYA, and Mihoko KATO. "Effect of PPARα Ligand on TNFα -Dependent Expression of EGF Receptor in Human Glioma Cell Line." Research Institute of Environmental Medicine, Nagoya University, 2002. http://hdl.handle.net/2237/2776.
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El-Ebissy, Eman. "Relationship between Metabolic Parameters and TNFα in the Peripartal Period in Ewes." Doctoral thesis, Universitätsbibliothek Leipzig, 2011. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-70051.
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Pregnancy toxaemia (ketosis) is a metabolic disease of ewes which occurs during the late gestation as a result of the inability of the pregnant ewe to maintain an adequate energy balance for the fast growing maternal fetal unit. As a result of energy defi-ciency mobilization of lipid reserves results in a doubling of the plasma free fatty acid (FFA) giving rise to fatty liver and increased ketone bodies β-hydroxybutyrate (BHB) in blood and urine. It is associated with a higher rate of mortality and causes severe economic losses.
The objective of this study was directed at investigating the relationship between metabolic parameters and cytokine TNFα, to check the interaction between the TNFα and fat metabolism in late pregnant ewes of different breeds, and whether TNFα play a role in the pathogenesis of pregnancy toxaemia, which may serve as marker to early diagnosis of the disease.
In this study, 29 pregnant and clinically healthy ewes (16 Merino, 13 Blackhead) were selected out of a flock of sheep. Blood samples were collected at 5, 3, and 1 week be-fore parturition (b.p.) and also 4 weeks after parturition (a.p.). The average numbers of lambs were 2.18 and 1.58 /ewe for Merino and Blackhead breeds respectively. The blood samples were analyzed for the following:
Concentration of metabolic parameters: glucose, insulin, free fatty acids (FFA), β-hydroxybutyrate (BHB), albumin, total protein (TP), iron (Fe), glutamat-dehydro-genase (GLDH), creatin kinase (CK), gamma-glutamyl-transferase (GGT), choles-terol, haptoglobin.
Haematological parameters: Haematocrite (HK), haemoglobin concentration (HB), erythrocyte count (EC), leukocyte count (LC), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC).
Cytokine TNFα by using ovine TNFα ELISA assay.
The results of glucose concentration of pregnant ewes showed significant increase (3.8 mmol/l) in five weeks b.p. and declined with advancing gestation (2.6 mmol/l) one week b.p. Insulin concentration remained constant with an average of 0.11 nmol/l b.p., and then significantly increased to 0.22 nmol/l four weeks a.p.
Maximal FFA concentrations were found at five weeks b.p. (976 µmol/l). The levels of FFA showed high levels b.p. compared with reference range (R.R. < 600 µmol/l), and the FFA levels significantly decreased postpartum (four weeks b.p.). while there was significant increasing (p<0.05) in the level of FFA in Merino sheep than in Black-head sheep b.p. On the other hand there was no significant difference a.p.
The mean values of BHB in all periods of sampling, period 1(5 w.b.p.), period 2 (3 w.b.p.), period 3 (1 w.b.p.), and period 4 (4 w.a.p.) were 0.37 mmol/l, 0.23 mmol/l, 0.17 mmol/l and 0.3 mmol/l respectively. The mean of BHB indicated normal levels of BHB before and after parturition compared to subclinical ketosis (BHB > 1 mmol/l) and clinical ketoses (BHB > 1.6 mmol/l), and there was a significant difference (p<0.05) in the values of BHB between Blackhead and Merino breeds before parturi-tion while there was no significant difference after parturition.
The concentration of TNFα showed elevated levels in all period of sampling before parturition. The TNFα values were 30.4 (17.2, 785.0) ng/ml (median, first, and third quartiles), 35.6 (13.6, 54.3), and 26.6 (13.0, 39.9) ng/ml in period 1(5 w.b.p.), period 2 (3 w.b.p.), and period 3 (1 w.b.p.) respectively. These values decreased to 19.1 (9.9, 33.8) ng/ml at 4 weeks after parturition.
Statistical analysis showed that there was a positive correlation between free fatty ac-ids and TNFα. This correlation means that adipose tissue produces TNFα causing insu-lin resistance, which stimulates the lipolysis and leads to an increase of circulatory free fatty acids levels.
It is concluded that fat mobilization occurs in the prepartum clinically healthy ewes with a significant increase in the levels of FFA, and also there is an increase in the proinflammatory cytokine TNFα at late gestation which predisposes ewes to pregnancy toxaemia and can aid in the diagnosis of the disease.
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Rauzy, Beyne Odile. "Régulation de la télomérase par le TNFα dans les cellules hématopoïétiques et leucémiques." Toulouse 3, 2006. http://www.theses.fr/2006TOU30029.
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L'objectif de notre travail a été d'étudier l'effet de l'exposition chronique au TNFα de cellules normales et leucémiques. Nous avons mis en évidence que l'exposition de cellules hématopoïétiques normales au TNFα pendant 15 jours induit une diminution de l'expression du gène et de l'activité de la télomérase (hTERT). Dans les cellules leucémiques, le TNFα induit un phénotype de sénescence corrélé à une attrition télomérique, une diminution de l'expression du gène et de l'activité d'hTERT ainsi qu'à l'apparition d'une instabilité chromosomique avec émergence de clones minoritaires cytogénétiquement anormaux. En présence de GM-CSF, cet effet est inhibé de manière significative et les cellules continuent de proliférer. La caractérisation des voies de signalisation impliquées dans la régulation négative de hTERT nous a permis de montrer que le TNFα génère la production de céramide ainsi que l'activation de JNK. Enfin, l'effet protecteur du GM-CSF est lié à sa capacité à inhiber non seulement la production de céramide, mais également la signalisation induite par le céramideThe aim of this study was to evaluate the effect of TNFα chronic exposition on normal and leukemic cells. Normal hematopoietic cells treated by TNFαduring 15 days have decreased levels of telomerase (hTERT) gene transcription and activity. In leukemic cells, TNFα induced a senescent phenotype correlated with telomeric attrition, hTERT gene expression and activity decrease, and emergence of chromosomal instability with new abnormal cytogenetic clones. This effect was inhibited by GM-CSF with normal cells growth. Cell signaling in hTERT negative regulation involved ceramide production and JNK activation. Protective effect of GM-CSF was associated to its capacity to inhibit ceramide production and signaling induced by ceramide
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Lehm, Manuel [Verfasser], and Regina [Akademischer Betreuer] Fluhrer. "Regulierte Intramembranproteolyse von TNFα durch SPPL2b / Manuel Lehm. Betreuer: Regina Fluhrer." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2016. http://d-nb.info/1112465502/34.
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Guillemette, Laetitia. "Implication du TNFα dans la résistance à l’insuline pendant la grossesse." Mémoire, Université de Sherbrooke, 2015. http://hdl.handle.net/11143/6009.
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Résumé : Le diabète gestationnel (DG), qui peut entraîner des conséquences importantes pour la mère et l’enfant, résulte d’un défaut de compensation de la sécrétion d’insuline par rapport à la résistance à l’insuline. Comme la grossesse représente en elle-même un modèle d’augmentation physiologique de la résistance à l’insuline, il est intéressant d’étudier et de caractériser les facteurs qui sont impliqués dans la résistance à l’insuline et, ultimement, dans le DG, chez la femme enceinte. Le Tumor necrosis factor alpha (TNFα) est soupçonné d’être un de ces facteurs, suite aux études effectuées chez les animaux et les populations humaines non enceintes, mais les résultats obtenus en grossesse sont encore controversés. Nous avons émis l’hypothèse que les niveaux circulants de TNFα sont associés au DG et à la résistance à l’insuline dans une large cohorte de femmes enceintes. Nous avons aussi investigué les variations des niveaux de TNFα en réponse à l’hyperglycémie provoquée par voie orale (HGPO) chez des femmes enceintes. Nous avons montré que de hauts niveaux de TNFα étaient liés à une résistance à l’insuline augmentée au 2e trimestre de la grossesse et ce, indépendamment de l’âge, de l’adiposité, de l’âge gestationnel, des triglycérides et des niveaux circulants d’adiponectine dans notre cohorte. De plus, les niveaux de TNFα varient différemment au cours de l’HGPO selon le statut de résistance à l’insuline. En effet, les niveaux de TNFα augmentent à 1h puis diminuent à 2h chez les femmes les plus sensibles à l’insuline, alors qu’ils diminuent tout au long du test chez les femmes les plus résistantes à l’insuline, mais restent en tout temps supérieurs aux niveaux mesurés chez les femmes les plus sensibles à l’insuline. Toutefois, les niveaux de TNFα n’étaient pas différents entre les femmes avec DG et celles normoglycémiques. De façon intéressante, la variation du TNFα pendant l’HGPO chez les femmes DG est similaire à celle chez les femmes avec haute résistance à l’insuline. Ces résultats suggèrent donc que le TNFα est indépendamment associé à la résistance à l’insuline en grossesse et que les voies inflammatoires peuvent contribuer aux dysfonctions glycémiques retrouvées en DG. // Abstract : Gestational diabetes mellitus (GDM), which can exert important impacts on mothers and offspring, results from an imbalance between insulin secretion capacity and insulin resistance. Pregnancy is a state of physiologically increased insulin resistance, providing a unique model to study and characterize biological factors linked to insulin resistance in humans and, ultimately, GDM, in pregnant women. Based on animal studies and analyses in non-pregnant populations, tumor necrosis factor alpha (TNFα) is suspected of being involved in insulin resistance, but results obtained from pregnant populations are still controversial. Our hypothesis was that circulating TNFα would be associated with GDM and insulin resistance in a large cohort of pregnant women. We also investigated dynamic variations of TNFα levels over the course of an oral glucose tolerance test (OGTT) in pregnant women. We showed that higher TNFα levels were associated with higher insulin
resistance at 2nd trimester of pregnancy, independent of age, adiposity, gestational age,
triglycerides and adiponectin levels in our cohort. Furthermore, TNFα levels varied
differently over the course of the OGTT according to insulin resistance status: they rose at 1h and then decreased at 2h in insulin sensitive women, whereas they consistently
decreased in insulin resistant women over the course of the test (even though they remained statistically higher than insulin sensitive women’s levels at each time point throughout the OGTT). However, TNFα levels were not different between GDM and non-GDM women. Interestingly, variation of TNFα levels over the course of the OGTT in GDM women followed the same pattern as the variation observed in OGTT in women classified with high insulin resistance. Those results suggest that circulating TNFα is independently associated with insulin resistance in pregnancy and that inflammatory pathways might contribute to glycemic dysregulation observed in GDM.
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Cottin, Vincent. "Signalisation intracellulaire par le récepteur CD120a pour le TNFα : rôle de la phosphorylation du domaine intracellulaire de CD120a dans la régulation des effets biologiques cellulaires du TNFα." Lyon 1, 2001. http://www.theses.fr/2001LYO1T026.
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Azria, David. "Association du facteur de nécrose tumorale (TNFα) et de la radiothérapie dans les cancers digestifs exprimant l'antigène carcinoembryonnaire (ACE) : intérêts d'un anticorps bispécifique anti-ACE/anti-TNFα." Montpellier 1, 2004. http://www.theses.fr/2004MON1T005.
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LE FACTEUR DE NECROSE TUMORALE ALPHA (TNFalpha) A MONTRE UN EFFET RADIOSENSIBILISANT DANS PLUSIEURS MODELES IN VITRO ET IN VIVO. EN CLINIQUE, SON UTILISATION SYSTEMIQUE A ETE MARQUEE PAR UNE TOXICITE MAJEURE. NOTRE METHODE DE CIBLAGE PAR LES ANTICORPS BISPECIFIQUES (AcBs) A PERMIS DE DELIVRER LE TNFalpha AU SEIN DE LA TUMEUR EN CIBLANT L'ANTIGENE CARCINOEMBRYONNAIRE (ACE). LE PREMIER OBJECTIF A ETE DE MONTRER L'EFFET RADIOSENSIBILISANT DU TNFalpha IN VITRO DANS DIFFERENTS MODELES DE CANCERS DIGESTIFS EXPRIMANT L'ACE EN ESSAYANT D'ANALYSER LE MECANISME IMPLIQUE, EN PARTICULIER, CONCERNANT LE CYCLE CELLULAIRE. LE SECOND OBJECTIF A ETE DE TRANSPOSER CES RESULATS IN VIVO DANS DIFFERENTS MODELES PRE-CLINIQUES EN UTILISANT UN AcBs ANTI-ACE/ANTI-TNFalpha. IN VITRO, NOUS AVONS MONTRE UN EFFET ADDITIF DE L'ASSOCIATION RADIOTHERAPIE (RT) + TNFalpha DANS DEUX MODELES DE TUMEUR HUMAINE EXPRIMANT L'ACE : LES LIGNEES COLIQUE LS174T ET PANCREATIQUE BxPC-3. APRES TRAITEMENT PAR LE TNFalpha, L'ETUDE DU CYCLE CELLULAIRE A MIS EN EVIDENCE UNE DIMINUTION DE L'ARRET EN G2 RADIO-INDUIT ET DE LA PHASE S AU DEPEND D'UNE AUGMENTATION DU NOMBRE DE CELLULES DANS LA PHASE G1. IN VIVO, DES SOURIS NUES GREFFEES ONT RECU DIFFERENTS TRAITEMENTS : SERUM PHYSIOLOGIQUE (NaCI), TNFalpha, AcBs, TNFalpha + AcBs, RT + NaCI, RT + TNFalpha + AcBs. UNE DIFFERENCE SIGNIFICATIVE DU DELAI DE PROGRESSION TUMORALE A ETE MISE EN EVIDENCE ENTRE LE GROUPE RT + NaCI ET LE GROUPE RT + AcBs + TNFalpha. DES EXPERIENCES AVEC DES SOURIS TRANSGENIQUES POUR L'ACE GREFFEES AVEC DES TUMEURS COLIQUES MURINES TRANSFECTEES AVEC LE GENE DE L'ACE ONT MONTRE UN DELAI DE PROGRESSION TUMORALE NETTEMENT INFERIEUR DANS LE GROUPE RT + TNFalpha HUMAIN + AcBS DONT DEUX GUERISONS. DES EXPERIENCES UTILISANT UN TNFalpha MURIN SONT EGALEMENT EN COURS AFIN D'EVALUER TOUT LE POTENTIEL THERAPEUTIQUE ET LES TOXICITES LIMITANTES DE CETTE STRATEGIE DANS UN MODELE ANIMAL IMMUNOCOMPETENT AVANT L'OUVERTURE D'UNE ETUDE CLINIQUE DE PHASE I.
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Ivagnes, Alexandre. "Valeur prédictive du récepteur NKp30 dans la réponse à l’imatinib mesylate des tumeurs stromales gastrointestinales et identification d’un nouveau mécanisme inhibiteur des cellules Natural Killer par la voie TNFα/TNFR2/BIRC3/TRAF1." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS237/document.
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Depuis ces 10 dernières années, l’immunothérapie est à l’avant-garde de la thérapie anticancéreuse. Les cellules Natural Killer (NK) font partie du système immunitaire inné et possèdent la capacité unique de lyser les cellules tumorales sans activation préalable par un antigène spécifique. Elles jouent un rôle majeur dans le contrôle de plusieurs cancers hématologiques et solides dont les tumeurs stromales gastrointestinales (GIST). Leur activation dépend de l’équilibre entre leurs récepteurs activateurs et inhibiteurs. Les Natural Cytotoxicity Receptors (NCR) font partis des récepteurs activateurs les plus importants dans leur reconnaissance des cibles et comprennent le NKp30, NKp44 et NKp46. Le NKp30 possède 3 isoformes: NKp30a et NKp30b sont immunostimulantes induisant la sécrétion d’Interféron (IFN) γ et de Tumor necrosis factor (TNF) α alors que NKp30c est immunosuppressive favorisant la production d’interleukine 10 (IL-10). L’IFNγ est un puissant activateur des cellules immunitaires tandis que l’IL-10 est une cytokine anti-inflammatoire. Le TNFα a été décrit initialement comme un facteur sérique induisant la nécrose des tumeurs, cependant son rôle a depuis été élargi à des fonctions homéostatiques. De nombreuses études laissent à penser que les fonctions antitumorales des cellules NK ne se limitent pas à l’élimination des cellules tumorales. Malgré les progrès importants réalisés dans la compréhension des cellules NK, de nombreux travaux sont encore à mener pour exploiter pleinement leur potentiel antitumoral.Notre équipe a démontré l’importance capitale des cellules NK dans les GIST. Ainsi l’infiltrat NK prédit la survie sans progression des patients. De plus nous avons montré que l’expression préférentielle de l’isoforme immunosuppressive NKp30c impactait négativement le pronostic des patients GIST. Suite à ces résultats, nous avons cherché à mieux caractériser l’impact des isoformes du récepteur NKp30 chez les patients GIST en réponse à l’IM. Dans un premier temps, nous avons démontré qu’un haut ratio d’expression entre NKp30b et NKp30c prédisait une meilleure réponse à l’imatinib mesylate (IM, un inhibiteur de tyrosine kinase, traitement de référence des GIST) et que l’expression des isoformes de NKp30 impactait l’environnement cytokinique de la tumeur. De plus, nous avons établi pour la première fois le lien entre la présence de ligands solubles de NKp30, B7 Homolog 6 soluble (sB7-H6) et BCL2 Associated Athanogene 6 soluble (sBAG6), et la diminution de la survie sans évènement des patients GIST traités à l’IM.Malgré l’infiltration immunitaire de nombreuses tumeurs, les fonctions antitumorales des lymphocytes sont inhibées par le microenvironnement tumoral. Ainsi, nous avons étudié quelles voies de signalisation étaient associées à l’inhibition des cellules NK présentes dans cet environnement. Pour cela, nous avons réalisé un microarray à partir des cellules NK infiltrant les GIST et avons mis en évidence le rôle délétère de la voie TNFα/TNF Receptor 2/Baculoviral IAP Repeat Containing 3 (BIRC3)/TNF Receptor Associated Factor 1 (TRAF1) dans la fonctionnalité des cellules NK. En effet, l’activation de cette voie dans les cellules NK entraine la diminution de la transcription du gène du récepteur activateur NKp46 ainsi que son expression membranaire. Cette diminution était corrélée avec l’expression de l’isoforme NKp30c. Par ailleurs, nous avons pu mettre en évidence chez la souris que le TNFα facilitait la dissémination métastatique de la lignée tumorale sensible aux cellules NK B16F10.Nos résultats sur les cellules NK ont renforcé leur grand potentiel en tant que cible thérapeutique pour l’immunothérapie anticancéreuse. En effet, l’importance du récepteur NKp30 et de ses isoformes dans la prédiction de la réponse à l’IM dans les GIST et la mise en évidence d’un nouveau mécanisme inhibiteur des cellules NK par la voie TNFα/TNFR2/BIRC3/TRAF1 ouvrent la voie à de nouvelles stratégies dans le traitement des cancersOver the last 10 years, immunotherapy has been at the forefront of cancer therapy. Natural Killer (NK) cells are part of the innate immune system and have the unique ability to lyse tumor cells without any antigen specific priming. They have a key prognostic role in several hematological and solid cancers including gastrointestinal stromal tumors (GIST). A balance between activating and inhibitory receptors triggers NK cell activation. Natural cytotoxicity receptors (NCR) are among the most clinically relevant activating receptors and include NKp30, NKp44 and NKp46. NKp30 can be expressed in 3 different isoforms: NKp30a and NKp30b are both immunostimulatory, inducing interferon (IFN) γ and tumor necrosis factor (TNF) α secretion whereas NKp30c is immunosuppressive, producing interleukin 10 (IL-10). IFNγ is a potent activator of immune cells whereas IL-10 is an anti-inflammatory cytokine. TNFα was first described as a serum factor, inducing tumor necrosis but its role has since been broadened to homeostatic functions. Ample evidence suggests that anti-tumor functions of NK cells are tightly regulated and expand far beyond the simple killing of malignant cells. Despite the tremendous progress in understanding NK cell biology, further work is warranted to fully exploit the anticancer potential of these cells.Our group demonstrated the crucial role that NK cells have in GIST. Indeed, NK cell infiltrate positively correlates with progression-free survival. Moreover, we showed that the preferential expression of the immunosuppressive isoform NKp30c, negatively impacts the clinical outcome of GIST patients. To further extend these observations, we explored the influence of various NKp30 isoforms in GIST patients.Firstly, we revealed that a high ratio between the expression of NKp30b and NKp30c isoforms predicted a stronger imatinib mesylate (IM) response (a tyrosine kinase inhibitor, TKI – first line standard of care in GIST) and that tumor cytokine milieu is modified following NKp30 isoform expression. Furthermore, we demonstrated a link between the presence of soluble ligands of NKp30, soluble B7 Homolog 6 (sB7-H6) and soluble BCL2 Associated Athanogene 6 (sBAG6), and a decrease in event-free survival in IM-treated GIST patients.Despite the presence of immune infiltration in many tumors, antitumor functions of lymphocytes are inhibited by the tumor microenvironment. Thus, we explored which signaling pathways were associated with NK cell inhibition in the tumor microenvironment. To do so, we performed a microarray from GIST infiltrating NK cells which highlighted the deleterious effect of TNFα/TNF Receptor 2/Baculoviral IAP Repeat Containing 3 (BIRC3)/TNF Receptor Associated Factor 1 (TRAF1) pathway on the function of NK cells. Next, we demonstrated that activation of this pathway in NK cells decreased gene transcription and protein expression of the activating receptor NKp46 (also called Natural Cytotoxicity Triggering Receptor 1 NCR1). This decrease positively correlated with NKp30c isoform expression. Moreover we showed that in mice, TNFα increases the metastatic dissemination of the NK sensitive tumor cell line, B16F10.Results from our research on NK cells strengthen the potential of NK cells as a therapeutic target for anti-tumor immunotherapy. Taken together, this thesis demonstrates the key role of the NKp30 receptor and its isoforms in the IM therapy as predictive marker in GIST response and describes for the first time a new NK cell inhibitory mechanism via the TNFα/TNFR2/BIRC3/TRAF1 pathway, paving the way for novel therapeutic strategies in cancer treatment
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Bazin, Thomas. "Microbiote intestinal et inflammation : prédiction de la réponse aux anti-TNFα dans les maladies inflammatoires chroniques et modulation de la croissance bactérienne in vitro en réponse au TNFα." Thesis, Bordeaux, 2018. http://www.theses.fr/2018BORD0285/document.
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L’interface hôte/microbiote intestinal est un système d’interactions complexes dont le déséquilibre est associé au développement des maladies inflammatoires chroniques. Les traitements anti-TNFα sont très efficaces dans ces maladies, mais seulement chez certains patients. L’objectif de ce travail était de rechercher un lien entre composition du microbiote intestinal et réponse aux traitements anti-TNFα dans deux types de maladies inflammatoires chroniques, les spondyloarthrites et les maladies inflammatoires chroniques de l’intestin. Nous avons retrouvé des variations de la composition du microbiote intestinal après traitement par anti-TNFα chez des patients atteints de spondyloarthrite et avons identifié un nœud taxonomique prédictif de la réponse thérapeutique à trois mois. Ce nœud taxonomique, l’ordre des Burkholderiales, étant ainsi un biomarqueur potentiellement utilisable en pratique clinique, nous avons déposé une demande de brevet européen, qui est en cours d’instruction. Ce travail a été poursuivi par un nouveau protocole de recherche clinique incluant des patients atteints de spondyloarthrites mais aussi de maladies inflammatoires chroniques intestinales. Ce protocole est financé par le CHU de Bordeaux dans le cadre de l’Appel d’Offre Interne. Il permettra de valider les hypothèses de notre premier travail, en réalisant notamment des PCR quantitatives utilisant des amorces spécifiques de l’ordre des Burkholderiales. Nous avons de plus retrouvé in vitro pour la première fois à notre connaissance une modulation de la croissance bactérienne chez Bacteroides fragilis en réponse au TNFα humainThe host/gut microbiota interface is a system of complex interactions whose imbalance is associated with the development of chronic inflammatory diseases. Anti-TNFα treatments are very effective in these diseases, but only in some patients. The purpose of this work was to find a link between the composition of the intestinal microbiota and clinical response to anti-TNFα treatments in two types of chronic inflammatory diseases, spondyloarthritis and inflammatory bowel disease. We found variations in the composition of the intestinal microbiota after treatment with anti-TNFα in patients with spondyloarthritis and identified a taxonomic node predictive of the therapeutic response at 3 months. This taxonomic node, the Burkholderiales order, being a biomarker potentially usable in clinical practice, we have filed a European patent application, which is currently under investigation. This work was continued by a new clinical research protocol including patients with spondyloarthritis but also with inflammatory bowel diseases. This protocol is funded by the Bordeaux University Hospital as part of the internal call for tenders. It will validate the hypotheses of our first work, notably by performing quantitative PCRs using specific primers targeting the order of Burkholderiales. In vitro, we have also found for the first time, to our knowledge, a modulation of bacterial growth in Bacteroides fragilis in response to human TNFα
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Pichette, Stephanie. "Engineering Novel TNFα-armed Oncolytic Viruses for Combination Immunotherapy with SMAC Mimetics." Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/35513.
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Small molecular Inhibitor of Apoptosis (IAP) antagonists, known as Smac mimetic compounds (SMCs), are a novel class of anti-cancer drugs currently undergoing clinical trials. SMCs were designed to mimic the function of the pro-apoptotic protein, Smac, which directly depletes cells of cIAP1 and cIAP2, and consequently renders tumour cells sensitive to death in the presence of proinflammatory ligands such as TNFα. The Korneluk lab recently reported that SMCs synergize with the attenuated oncolytic virus Vesicular stomatitis virus (VSVΔ51) by eliciting an enhanced immune response in mice, such that the combined therapy is vastly superior to stand-alone therapies. To improve on this SMC-mediated synergistic response, I generated variants of TNFα-armed VSVΔ51. Due to high ectopic expression of TNFα in infected cells, a five times lower viral dose of TNFα-armed VSVΔ51 combined with SMC treatment was sufficient to improve the survival rate as compared to SMC and VSVΔ51 co-therapy. This improved synergistic response is attributed to a bystander effect whereby the spread of TNFα from infected cells leads to the death of neighbouring, uninfected cells in the presence of a SMC. In addition, the double treatment induced vasculature collapse in solid tumours, revealing another mechanism by which cytokine-armed VSVΔ51 in combination with a SMC can induce cancer cell death. This approach demonstrates great potential for engineered oncolytic virus and SMCs as a new combination immunotherapy for cancer treatment.
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Lacerda, Lydia. "Signalling pathways involved in TNFα-induced cytoprotection : role of reactive oxygen species." Master's thesis, University of Cape Town, 2005. http://hdl.handle.net/11427/3414.
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Includes bibliographical references (leaves 73-89).Tumour necrosis factor alpha (TNFa) is a pleiotropic cytokine which has both beneficial and deleterious effects. It has previously been shown in our laboratory that TNFa can mimic ischemic preconditioning (IPC). However, the signalling pathways involved in this protection remain incompletely understood. One potential protective pathway involves the generation of reactive oxygen species (ROS), which are known to be activated by TNFa. It was therefore hypothesized that TNFa-induced cytoprotection requires the generation of ROS. In addition, it was postulated that this ROS generation originates in the mitochondria.
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Hsu, Kuo-Sheng. "TRANSCRIPTIONAL AND TRANSLATIONAL REGULATION BY TNFα AND IFNα CONTROLS MULTIPLE CELLULAR FUNCTIONS." Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1428021369.
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Shibuya, Hideyuki. "TNFα, PDGF and TGFβ synergistically induce synovial lining hyperplasia via inducible PI3Kδ." Kyoto University, 2015. http://hdl.handle.net/2433/199195.
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Bitam, Sara. "Nouveaux correcteurs de la protéine F508del-CFTR dans le contexte de la mucoviscidose." Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015PA05T034.
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La mucoviscidose est la maladie génétique récessive la plus fréquente dans les populations caucasiennes. Elle est dûe à des mutations dans le gène CFTR qui code pour une protéine qui a une fonction canal chlorure et qui est exprimée au pôle apical des épithéliums sécrétoires. La mutation la plus fréquente F508del altère le repliement de la protéine, induisant sa dégradation précoce par le protéasome et son absence à la membrane plasmique. La recherche fondamentale se focalise sur la protéine mutée et cherche à découvrir des molécules capables d’adresser celle-ci au pôle apical des cellules épithéliales où elle pourra remplir sa fonction de canal chlorure. Au sein du laboratoire, nous nous intéressons aux interactions de la protéine CFTR/ F508del-CFTR avec d’autres protéines. Nous avons déjà montré l’existence d’une interaction non voulue entre F508del-CFTR et un filament intermédiaire, la cytokératine 8. En combinant une approche in-silico et du criblage haut débit, nous avons identifié des molécules capables d’interrompre ces interactions. Des tests fonctionnels sur des lignées cellulaires ainsi que sur des modèles murins ont montré une restauration de la fonction canal chlorure après traitements avec ces molécules. Au cours de ma thèse, je me suis intéressée à l’une d’entre elles qui est la molécule « c407 ». L’objectif de ma thèse était de comprendre les mécanismes d’action de cette molécule. J’ai également évalué l’efficacité des traitements actuels dans le contexte des allèles complexes de F508del-CFTR. Dans une seconde partie de ma thèse, j’ai étudié l’effet d’une cytokine (TNFα) sur la protéine mutée F508del-CFTR. De façon inattendue, j’ai observé que le TNFα, à des concentrations physiologiques, corrige le défaut de routage de la protéine F508del-CFTR. Cette observation pourrait expliquer une fonction résiduelle de la F508del-CFTR chez certains patients atteints de mucoviscidose. En conclusion, mes travaux ont permis de préciser les mécanismes d’action d’un correcteur et de découvrir un effet inattendu d’une cytokine pro-inflammatoire. Ces travaux permettent de relier la correction d’un défaut de routage au processus inflammatoire ouvrant ainsi un nouveau champ d’investigationCystic fibrosis is due to the loss of epithelial chloride transport caused by mutations in the CFTR gene, the most frequent mutation being F508del. One of the strategies developed to find new treatment for Cystic fibrosis (CF) is to discover compounds that correct the trafficking of F508del-CFTR to the plasma membrane. Using hypothesis-driven approach and combining modeling of NBD1, molecular docking and functional assays, we identified 4 compounds that correct F508del-CFTR function in cells (including human primary bronchial cells in culture) and F508del mice. New correctors probably act by interrupting the interaction between F508del-CFTR with keratin 8 (Odolczyk et al EMBO Mol Med 2013). During my PhD, I focused on one of those molecules, the "c407" molecule. The aim of my thesis was to investigate the mechanisms of action of this molecule. I have also evaluated the effectiveness of current treatments in the context of complex alleles F508del-CFTR. In the second part of my thesis, I studied the effect of a cytokine (TNFα) on the protein F508del-CFTR. Unexpectedly, I observed that the TNFα at physiological concentrations, corrects the trafficking of F508del-CFTR protein. This observation could explain a residual function of F508del-CFTR in some CF patients. In conclusion, my thesis helped to clarify the mechanisms of action of new correctors of F508del-CFTR
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Acosta, Colmán María Isabel. "Biomarcadores de respuesta a la terapia anti-TNFα en pacientes con Artritis Reumatoide." Doctoral thesis, Universitat Autònoma de Barcelona, 2012. http://hdl.handle.net/10803/117592.
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Langton, Amy Jean. "The role of TRUSS in TNFα-TNFRI signalling : implications for inflammatory lung diseases." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608019.
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Medina-Tato, David A. "Role of phosphoinositide 3-kinase in TNFα signalling in A549 lung alveolar cells." Thesis, University of Bath, 2007. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441522.
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Ben, Nasr Nesrine. "Optimisation de méthodes de criblage virtuel et synthèse de molécules à visée thérapeutique pour le traitement des maladies auto-immunes." Thesis, Paris, CNAM, 2014. http://www.theses.fr/2014CNAM0907.
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Le criblage virtuel est de plus en plus utilisé dans les programmes de recherche de nouveaux principes actifs. L’augmentation considérable du nombre de structures résolues a favorisé le recours aux méthodes basées sur la structure de la cible comme le docking. Néanmoins, le choix de la/des structure(s) à utiliser demeure une question d’actualité. Pour tenter d'apporter une réponse, les résultats des études de docking menées sur la banque d’évaluation de référence (DUD) ont été analysés en prenant en compte les propriétés des sites de liaisons des structures de référence. D’intéressants résultats ont été obtenus mettant en évidence l'influence du volume et de l’ouverture des sites actifs sur les performances des méthodes. Ces critères de sélection simples et peu coûteux peuvent servir pour l’optimisation de protocoles de docking.Alors qu’aucune petite molécule inhibitrice du TNFα n’est actuellement commercialisée, l’application d’un protocole hiérarchique de criblage virtuel/in vitro, a permis d’identifier des touches actives. L’une d’elle, de squelette benzènesulfonamide a fait l’objet de pharmacomodulation en vue d’obtenir des analogues optimisés. Vingt molécules inédites ont été synthétisées et testées in vitro et certaines ont montré une activité intéressante. L’ensemble des données obtenues apportent des éléments importants de relation structure-activité. Ces résultats peuvent être exploités pour la conception de molécules innovantes ciblant le TNFα ce qui serait une avancée prometteuse pour le traitement des pathologies liées à une surproduction de cette cytokine comme la polyarthrite rhumatoïde et la maladie de CrohnVirtual screening is widely used in drug discovery programs. The increasing number of resolved structures favored the use of Structure Based Virtual Ligand Screening methods like docking. Nevertheless, the choice of the structure(s) used as reference remains a topical issue when several are available. In this work, DUD database docking results were analyzed taking into account the properties of the query structure(s) binding sites. Interesting results were obtained highlighting the influence of active site volume and opening on methods performances. These simple and inexpensive “binding site properties-based” guidelines could be helpful to optimize future docking protocols.Despite important effort, no active small molecule targeting TNFα has been released so far. The use of a virtual/ in vitro hierarchical approach screening allowed identifying some active hits. Starting from one of them with a benzenesulfonamide structure, pharmacomodulation was achieved in order to obtain optimized analogs. Twenty new chemical derivatives with an original structure were synthesized and tested in vitro. Some of them exhibited an interesting activity. Moreover, data obtained provide important elements of structure-activity relationship. These results could constitute the basis for innovative small molecule TNFα-targeted therapeutics which would be a promising step for the treatment of diseases related to overproduction of this cytokine such as rheumatoid arthritis and Crohn's disease
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Fluckiger, Aurélie. "Effet anti-tumoral de l'acide docosahexaénoïque : implication des microARNs et du TNFalpha." Thesis, Dijon, 2015. http://www.theses.fr/2015DIJOS042/document.
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L’acide docosahexaénoïque (DHA) est un acide gras polyinsaturé oméga-3 avec des propriétés anti-inflammatoires et anti-tumorales. L’effet du DHA dans le cadre du cancer colorectal pourrait être la conséquence d'une action anti-proliférative directe sur les cellules cancéreuses et de sa capacité à réduire l’inflammation propice au développement de la tumeur. Le Tumor Necrosis Factor-alpha (TNFa) est une cytokine pro-inflammatoire et présente des effets paradoxaux. En fonction du contexte cellulaire, le TNFa activera une voie de signalisation dépendante de la kinase RIP1 engageant la cellule cancéreuse vers la prolifération ou la mort cellulaire. Notre objectif fut d'évaluer le rôle du TNFa dans l'effet anti-prolifératif du DHA sur des cellules cancéreuses coliques et de préciser les mécanismes moléculaires régulant l'expression de cette cytokine. Le DHA induit l'expression de TNFa et sa sécrétion par les cellules cancéreuses. Nous avons montré que des anticorps neutralisant l'action autocrine du TNFa sur les cellules cancéreuses prévenait l'effet pro-apoptotique du DHA et abolissait l'effet anti-cancéreux observé dans des souris nude avec tumeurs HCT-116 sous régime DHA. L’induction de l'expression de TNFa par le DHA prend son origine à un niveau post-transcriptionnel par la répression du microARN miR-21 perdant sa capacité à dégrader l'ARNm TNFa. Le DHA par l'activation des kinases AMPKa et RIP1 déclenche la translocation nucléaire du facteur de transcription FOXO3a se fixant sur le promoteur miR-21 et diminuant l’expression de ce microARN. Nos travaux mettent en évidence un nouveau mécanisme moléculaire soutenant l'action anti-tumorale du DHADocosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid with anti-inflammatory and anti-tumoral properties. The anti-tumor effect of DHA in colorectal cancer might be attributed to direct anti-proliferative action on cancer cells and to its ability to reduce inflammatory status involved in tumor growth. Tumor Necrosis Factor-alpha (TNFa) is an inflammatory cytokine with paradoxical effect in cancer biology. According to the cellular context, TNFa activates RIP1 kinase dependent signaling pathway leading to proliferation or cell death. Our aim was to evaluate the role of TNFa in anti-proliferative effect of DHA in colon cancer cells and to precise the molecular mechanisms regulating TNFa expression.DHA treatment increased TNFa expression and secretion by cancer cells. We have shown that neutralization of autocrine TNFa action prevented the pro-apoptotic effect of DHA colon cancer cells and abolished anti-cancer effect in tumor HCT-116 bearing nude mice fed a DHA-enriched diet. Induction of TNFa expression by DHA occured at post-transcriptional level through microRNA miR-21 repression reducing its ability to induce TNFa mRNA degradation. DHA activates AMPKa and RIP1 kinases triggering nuclear translocation of the transcription factor Foxo3a which bound to miR-21 promoter and repressed the microRNA expression. Our works highlight a new molecular mechanism supporting the anti-cancer action of DHA
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Arens, Katharina [Verfasser]. "Therapeutic anti-TNFα antibodies differentially affect Leishmania infection of primary human macrophages / Katharina Arens." Mainz : Universitätsbibliothek Mainz, 2018. http://d-nb.info/116049147X/34.
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Tilwani, Reshma Kishan. "Low oxygen tension modulates the effects of TNFα and fibronectin fragments in compressed chondrocytes." Thesis, Queen Mary, University of London, 2017. http://qmro.qmul.ac.uk/xmlui/handle/123456789/30950.
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Oxygen tension and biomechanical signals are factors that regulate inflammatory mechanisms in chondrocytes. We examined whether low oxygen tension influenced the cells response to TNFα and dynamic compression. Chondrocyte/agarose constructs were treated with varying concentrations of TNFα (0.1 to 100 ng/ml) and cultured at 5% and 21% oxygen tension for 48 hours. In separate experiments, constructs were subjected to dynamic compression (15%) and treated with TNFα (10 ng/ml) and/or L-NIO (1 mM) at 5% and 21% oxygen tension using an ex-vivo bioreactor for 48 hours. Markers for catabolic activity (NO, PGE2) and tissue remodelling (GAG, MMPs) were quantified by biochemical assay. ADAMTS-5 and MMP-13 expression were examined by real-time qPCR. 2-way ANOVA and a post hoc Bonferroni-corrected t-test were used to analyse data. TNFα dose-dependently increased NO, PGE2 and MMP activity (all p < 0.001) and induced MMP-13 (p < 0.05) and ADAMTS-5 gene expression (p < 0.01) with values greater at 5% oxygen tension than 21%. The induction of catabolic mediators by TNFα was reduced by dynamic compression and/or L-NIO (all p < 0.001), with a greater inhibition observed at 5% than 21%. The stimulation of GAG synthesis by dynamic compression was greater at 21% than 5% oxygen tension and this response was reduced with TNFα or reversed with L-NIO. The present findings revealed that TNFα has dose-dependent catabolic activities and increased production of inflammatory mediators at low oxygen tension. Dynamic compression or the NOS inhibitor downregulated the inflammatory effects induced by TNFα, linking both types of stimuli to reparative activities. Future therapeutics should develop oxygen-sensitive antagonists which are directed to interfering with the TNFα induced pathways.
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Caux, Christophe. "Étude du rôle du TNFα sur la régulation de la myélopoïèse humaine in vitro." Lyon 1, 1992. http://www.theses.fr/1992LYO1H002.
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Wünsch, Camile. "Influência de polimorfismos em genes do processo inflamatório na doença arterial coronariana." reponame:Repositório Institucional da UNIVATES, 2016. http://hdl.handle.net/10737/1581.
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CAPES
Introdução: A doença arterial coronariana (DAC) é a principal causa de morbidade e mortalidade no mundo, sendo caracterizada como uma doença inflamatória crônica, multifatorial, cuja fisiopatologia é a aterosclerose. Considerando a alta herdabilidade da doença, vários polimorfismos genéticos vêm sendo estudados e associados com o surgimento da DAC e, entre eles, destacam-se variantes nos genes CD14, TLR4, NFKB1 e TNFα, os quais regulam a via de sinalização celular do sistema imune inato e desencadeiam o processo inflamatório na DAC. Objetivo: O objetivo principal deste estudo é verificar a possível associação de polimorfismos nos genes CD14 (rs2569190), TLR4 (rs4986790 e rs4986791), NFKB1 (rs28362491) e TNFα (rs1800629 e rs361525) com a DAC. Metodologia: A amostra foi composta por 707 indivíduos adultos submetidos ao exame de cateterismo cardíaco no Hospital Bruno Born, de Lajeado, RS. Todos os indivíduos assinaram um termo de consentimento livre e esclarecido e responderam a um questionário semiestruturado. Os indivíduos foram classificados entre casos e controles, por um médico cardiologista, com base no seguinte critério: presença de estenose, com comprometimento maior do que 50%, em pelo menos uma das artérias coronárias. Foram também coletadas amostras de sangue periférico para análises bioquímicas e moleculares. A extração de DNA foi realizada pelo método de salting out. Os polimorfismos dos genes CD14, TLR4 e TNFα foram genotipados pelo sistema de discriminação alélica TaqMan, em equipamento de reação em cadeia da polimerase (PCR) em Tempo Real (StepOnePlus®). O polimorfismo rs28362491, no gene NFKB1, foi amplificado através da técnica convencional de PCR. Resultados: Identificamos uma associação dos polimorfismos rs2569190, localizado no gene CD14, e rs28362491, no gene NFKB1, com a DAC. Além disso, foram detectados efeitos dos polimorfismos dos genes TLR4 e TNFα nos níveis glicêmicos e dos polimorfismos nos genes TLR4, NFKB1 e TNFα no perfil lipídico. Conclusão: Nossos achados sugerem a participação de polimorfismos nos genes CD14 e NFKB1 no desenvolvimento da DAC na nossa amostra, corroborando evidências prévias do envolvimento de genes do processo inflamatório nessa patologia.
Introduction: Coronary artery disease (CAD) is the main cause of morbidity and mortality in the world, being characterized as a chronic, multifactorial inflammatory disease, whose pathophysiology is atherosclerosis. Considering the high heritability of the disease, several genetic polymorphisms have been investigated and associated with CAD and, among them, there are variants in the CD14, TLR4, NFKB1 and TNFα genes, which regulate cell signaling pathways of the innate immune system and inflammatory process in CAD. Objective: The main objective of this study is to verify the association beteween polymorphisms in the CD14 (rs2569190), TLR4 (rs4986790 and rs4986791), NFKB1 (rs28362491) and TNFα (rs1800629 and rs361525) genes and CAD. Methods: The sample group was composed of 707 adult individuals, recruited at the time when they were bought in for coronary angiography procedures at the Hemodynamic Center of the Hospital Bruno Born, City of Lajeado, Rio Grande do Sul. The individuals were classified between cases and controls by a cardiologist, based on the following criteria: presence of stenosis, greater than 50% of the luminal diameter, in at least one of the coronary arteries. Peripheral blood samples were also collected for biochemical and molecular analyzes. DNA extraction was performed using the salting out method. The polymorphisms in the CD14, TLR4 e TNFα genes were genotyped by Taqman® allelic discrimination assays. The rs28362491 polymorphism in the NFKB1 gene was amplified by polymerase chain reaction (PCR). Results: We identified an association between the polymorphisms rs2569190, located in the CD14 gene, and rs28362491, located in the NFKB1 gene, and CAD. In addition, there were detected significant effects of TLR4 and TNFα gene polymorphisms on glycemic levels and TLR4, NFKB1 and TNFα gene polymorphisms on the lipid profile. Conclusion: Our findings suggest a role for the polymorphisms in CD14 and NFKB1 genes in CAD susceptibility in our sample, corroborating previous evidence of the envolviment of inflamotory process genes in this patology.
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Kramer, Katharina [Verfasser]. "Experimentelle Infektion von TNFα-transgenen [TNF-alpha-transgenen] Mäusen mit dem Virus der Bornaschen Krankheit : Charakterisierung der Entzündungsreaktion und der Virusreplikation / vorgelegt von Katharina Kramer." Gießen : DVG-Service, 2006. http://d-nb.info/994578830/34.
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Su, Baowei. "Treatment of cancer with combined chemo-gene therapy based on TNFα polyplexes and liposomal doxorubicine." Diss., lmu, 2011. http://nbn-resolving.de/urn:nbn:de:bvb:19-132398.
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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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Petitcollin, Antoine. "Pharmacocinétique et relation concentration-effet des anti-TNFα dans les maladies inflammatoires chroniques de l’intestin." Thesis, Rennes 1, 2019. http://www.theses.fr/2019REN1B032.
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Les anticorps thérapeutiques ont une pharmacocinétique complexe. Lorsque la masse antigénique augmente, les anticorps thérapeutiques sont éliminés plus vite ; ainsi une maladie active détermine une clairance élevée. De plus, les patients peuvent s’immuniser contre le médicament, produisant des anticorps responsables d’une élimination très accélérée. Dans ce travail, nous avons étudié la variabilité de la pharmacocinétique et de la relation concentration-effet des anti-TNFα dans les maladies inflam-matoires chroniques de l’intestin (MICI). Nous avons décrit par modélisation compartimentale la variabilité pharmacocinétique intra-individuelle de l’infliximab et étudié ses sources, démontrant l’étroite relation entre activité de la maladie et clairance. Nous avons également proposé un modèle capable de détecter les variations de clairance évocatrices d’immunisation indépendamment de la mise en évidence des anticorps anti-médicaments, permettant de s’affranchir du manque de sensibilité analytique de la recherche d’immunisation.Les variations de pharmacocinétique au cours du temps ont été confrontées à la réponse clinique, et nous avons montré que la clairance était prédictive de la réponse en induction et au cours de la désescalade thérapeutique. Nous avons donc proposé que le monitoring des traitements puisse inclure un suivi de l’évolution de la clairance comme marqueur précoce de l’activité de la maladie. Enfin, nous avons montré que l’exposition cumulée était relié au risque d’infection opportuniste dans les MICI. Cela pose les bases de recommandations concernant les modalités d’adaptations poso-logiques qui font actuellement défaut. L’ensemble des travaux présentés ici contribuent à améliorer notre connaissance de la pharmacologie des anti-TNFα et des anticorps thérapeutiques en général et ainsi à optimiser leur utilisation chez les patientsTherapeutic antibodies display complex pharmacokinetic properties. When the antigenic mass increases, they are eliminated faster, and thus an active disease is responsible for a fast clearance. Moreover, patients can produce antibodies to the drug, leading to a strongly accelerated clearance. In this work, we studied the variability of the pharmacokinetics and of the concentration-effect relationship of anti-TNFα antibodies in inflammatory bowel diseases (IBD). The intra-individual variability of infliximab was described using compartmental modelling, and the relationship between disease activity and clearance was demonstrated at the individual level. A model was built to detect clearance increases putatively linked to immunogenicity, independently from evidencing any anti-drug antibodies in blood samples, thus avoiding the analytical issues that hampers the detection of immunization. The time-varying pharmacokinetics was comfronted to the clinical response, showing that clearance was predicitive of the respsonse in induction and de-escalation settings. Therefore, it was hypothetized that monitoring the clearance could help the follow-up of the disease, as an early marker of disease activity and evolution. Last, it was shown that cumulated exposure to infliximab was linked to the risk of developping opportunistic infections. Based on this data, recommandations regarding the modalities of regimen adaptations could be built, that are currently lacking. All the work presented here contribute to enhance our knowledge of the pharmacology of anti-TNFα antibodies, but also of other therapeutic antibodies, and to improve their use in clinical settings
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Gerl, Markus [Verfasser]. "Untersuchungen über das Expressionsverhalten von Ro52 und TNFα in Monozyten beim Sjögren-Syndrom / Markus Gerl." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2008. http://d-nb.info/102333075X/34.
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BRITTO, Lidiane Regia Pereira Braga de. "Polimorfismos dos genes MBL2, IL-10 e TNFα em pacientes com leucemia aguda na infância." Universidade Federal Rural de Pernambuco, 2014. http://www.tede2.ufrpe.br:8080/tede2/handle/tede2/4699.
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The chemotherapy used in the treatment of acute leukemias (AL) in pediatric immune system, promoting the morbidity and mortality from infection during the induction phase of treatment, the first 50 days. However, questions remain about why some of these children develop severe and fatal infections. The occurrence of polymorphisms (SNPs) in regions associated with regulation of immune system components may be associated with proteins that indicate the recognition of pathogens, such as the mannose-binding lectin (MBL) and cytokine tumor necrosis factor alpha (TNFα) and interleukin 10 (IL-10). The aim of this study was to evaluate the association between susceptibility to infection of pediatric patients and the following polymorphisms: -550 promoter regions (alleles H / L), -221 (alleles X / Y) and structural exon 1 (alleles A / O) MBL2 gene, the promoter region -1082 (allele G / A), -819/-592 (allele C / T) of the IL-10 gene region and -308 (allele G / A) gene TNFα. The 225 patients were evaluated in the CEONHPE / HUOC-UPE. Of these, 84% (n = 189) were diagnosed with acute lymphoblastic leukemia (ALL). Overall group (AL), there was no association between the three polymorphic regions studied with febrile neutropenia (-550 H/L, p=0.912; -221 X/Y, p=0.471; exon 1 A/O, p=0.138), number of infectious events (-550 H/L, p=0.912; exon 1 A/O, p=0.741) and the risk of relapse (-550 H/L, p=0.588; exon 1 A/O, p=0.882). However, an association was observed between age and genotype AO of exon 1 in patients younger than 10 years in AL (p=0.027) and ALL (p=0.038). In conclusion, we can suggest that the pediatric patients younger than 10 years, carriers of the MBL2 genotype AO, that determine low oligomerization and compromised biological function of the protein may have immune response deficiency.
A quimioterapia utilizada no tratamento de leucemias agudas (LA) pediátricas deprime o sistema imune, favorecendo a morbidade e mortalidade por infecções durante a fase de indução do tratamento, ou seja, os primeiros 50 dias. Entretanto, permanecem duvidas sobre o porquê de algumas dessas crianças desenvolverem infecções severas e fatais. A ocorrência de polimorfismos (SNPs) em regiões promotoras e estruturais de genes de componentes do sistema imune pode estar associada ao padrão de reconhecimento de patógenos, a exemplo da Lectina Ligadora de Manose (MBL) e das citocinas Fator de Necrose Tumoral alfa (TNFα) e interleucina 10 (IL-10). O objetivo deste trabalho foi verificar uma possível associação entre a susceptibilidade à infecção nos pacientes pediátricos com os polimorfismos nas regiões promotoras -550 (alelos H/L), -221 (alelos X/Y) e estrutural éxon 1 (alelos A/O) do gene MBL2, das regiões promotoras -1082 (alelos G/A), -819/-592 (alelos C/T) do gene IL-10 e região -308 (alelos G/A) do gene TNFα. Foram avaliados 225 pacientes com LA em tratamento no CEONHPE/HUOC-UPE. Destes, 84%(n=189) tiveram o diagnóstico de Leucemia Linfoblástica Aguda (LLA). No grupo geral (LA), houve ausência de associação entre as três regiões polimórficas estudadas do gene MBL2 com a neutropenia febril (-550 H/L, p=0,912; -221 X/Y, p=0,471; éxon 1 A/O, p=0,138), número de eventos infecciosos (-550 H/L, p=0,912; éxon 1 A/O, p=0.741) e o risco de recaída (-550 H/L, p=0,588; éxon 1 A/O, p=0,882). Entretanto, observou-se que o genótipo AO do gene MBL2 foi associado aos pacientes pediátricos com LA (p=0,027) e LLA (p=0,038) que apresentavam idade abaixo de 10 anos. Com relação aos polimorfismos dos genes IL-10 e TNFα não foi observada associação com as mesmas situações clínicas anteriormente referidas e nem com a idade dos pacientes. Em conclusão, podemos sugerir que os pacientes pediátricos com idade abaixo de 10 anos e portadores do genótipo AO do gene MBL, que determina baixa oligomerização e função biológica comprometida da proteína podem apresentar deficiência na resposta imune.
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Nur, Zeineba. "Optimering av ELISA för analys av anti-TNFα antikroppar i serumprover från patienter med inflammatorisk tarmsjukdom." Thesis, Örebro universitet, Hälsoakademin, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-10942.
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SAMMANFATTNING Crohns sjukdom/CD och ulcerös kolit/UC är de två mest kända sjukdomarna som lyder under samlingsnamnet inflammatoriska tarmsjukdomar/IBD. Sjukdomarna karaktäriseras av kroniska diarréer där blodiga diarréer är ett kardinal symtom vid UC. Uppkomstmekanismen för IBD är okänd men immunologiska processer spelar en betydande roll för patogenesen av sjukdomarna. Sjukdomarna kan uppstå på grund av en obalans mellan pro-inflammatoriska och anti-inflammatoriska cytokiner. Dessutom förekommer autoimmun reaktivitet riktade mot olika antigen t.ex. neutrofiler. Syftet med detta projekt var att sätta upp en metod för ELISA-analys av serumprover, för att kunna analysera om patienter med CD eller UC har ökade halter av neutraliserande antikroppar mot tumörnekrotisk faktor/TNFα i serum jämfört med friska kontroller. I studien analyserades 60 patientprover; 30 från patienter med CD, 30 från patienter med UC, för ökade halter av anti-TNFα antikroppar i serum jämfört med friska blodgivare med ELISA-teknik. De erhållna resultaten visade att det fanns ökad antikroppsreaktivitet mot TNFα framförallt hos UC patienter men även till viss del hos CD patienter. Vi kunde dock inte neutralisera dessa antikroppar med löslig rTNF. Med detta provmaterial kan man konstatera att ELISA-metoden har fungerat bra och det var också syftet med projektet. Man kan även konstatera att det är viktigt att säkerställa att det man mäter är specifikt för det man söker. Nyckelord: IBD, CD, UC, TNFα, ELISA, autoantikroppar.
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Sabbah, Bassam. "Modulation de la sécrétion de l'IL-10 et du TNFα au cours du syndrome d'hypersensibilité médicamenteuse." Rouen, 2014. http://www.theses.fr/2014ROUES049.
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Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug-induced reaction that involves both the skin and the viscera. Several herpesvirus family members including EBV or HHV-6 can be found reactivated coincidently with various clinical symptoms in DRESS. In addition, we have previously identified activated EBV specific cytotoxic CD8+ T cells as major actors in the pathophysiology of DRESS. Furthermore, gene expression profiling from DRESS patients revealed that IL-10 and TNFα were two of the most upregulated mRNA in PBMCs and in CD8+ T lymphocytes respectively. Interestingly, IL-10 plays a key role in the immunomodulation and EBV replication while TNFα is highly implicated in the inflammation process during DRESS. However, direct drug effect on cytokines secretion and its relationship with viral reactivation has not been studied. We thus measured IL-10 and TNFα secretion levels in DRESS patients’ serum, in control patients taking DRESS inducer drugs without adverse effect and B-LCL lines following incubation with DRESS inducer drugs for 72 hours. We analyzed the presence of IL-10 and TNFα by ELISA and FACS. We show that DRESS patients as well as patients taking drugs without adverse effect have an increase of IL-10 and TNFα in their serum at the onset of the disease. In vitro, we demonstrate that some DRESS inducer drugs namely SMX and VPA reduce significantly the IL-10 secretion in B-LCL from DRESS patients but not from healthy donors by sequestering IL-10 in the cytoplasm. Interestingly, the same observation was obtained for TNFα in DRESS patients and healthy donors B-LCL, with however differential effect depending of the drugs regarding the sequestering of TNFα also in the cytoplasm of B cells. The balance between IL-10 and TNFα is affected by DRESS inducer drugs specifically in DRESS patients and viral reactivation seems to play a key role in cytkine release. These findings allow a better understanding of the physiopathology of the DRESS syndrome and drug induced hypersensitivity.
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Teasdale, Jack Edward. "Influence of TNFα and cigarette smoke on endothelial dysfunction : interplay between shear stress and risk factors." Thesis, University of Bristol, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.682679.
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I have developed a model in which to examine factors that may affect endothelial erosion, a pathology that is responsible for approximately 25% of myocardial infarctions. Cigarette smoking is a risk factor for erosion; and long-term, heavy smokers have increased circulating markers of inflammation; therefore I have studied the interaction of cigarette smoke extract (CSE) and the inflammatory mediator tumour necrosis factor-alpha (TNFα) on endothelial dysfunction. Endothelial cells are mechanosensitive, with Kruppel-like factor (KLF) 2/4 and Nuclear response erythroid 2-like 2 (Nrf) Nrf2 mediating a large part of the atherop~otective effect of laminar shear stress in endothelial cells. I therefore studied endothelial dysfunction in oscillatory, normal laminar and elevated laminar shear stress in human coronary artery endothelial cells (HCAEC). TNFα robustly increased nuclear factor kappa-B (NFKB) responsive gene expression, which was suppressed with increasing magnitude of laminar shear stress. CSE did not activate the expression of NFKB responsive genes, but inhibited TNFα induction of NFKB regulated genes. CSE strongly increased the expression of Nrf2-regulated gene expression, which was further increased by the addition of TNFα; however, Nrf2 was not responsible for the reduction in NFKB signalling. Despite the reduction in NFKB gene expression, HCAECs under laminar shear stress lost adherence when treated with both TNFα and CSE a process that appears to be independent of MMP activity, apoptosis or necrosis. Treatment with Nrf2 agonists increased rather than protected against cell loss raising the possibility that uncontrolled Nrf2 expression is detrimental. In summary, I have for the first time created an in vitro model that utilizes risk factors for endothelial erosion and can mimic endothelial cell loss when combining CSE and TNFα. A reduction in inflammatory gene expression was not associated with increased cell survival, rather Nrf2 hyperactivation contributed to endothelial erosion.
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Santinon, François. "Rôle du TNFR2 exprimé à la surface des lymphocytes T régulateurs dans l’inflammation dépendante du TNFα." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCD006.
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La polyarthrite rhumatoïde (PR) est une maladie inflammatoire chronique d’étiologie inconnue. L’inflammation présente dans cette pathologie est fortement dépendante de la cytokine pro-inflammatoire qu’est le TNFα. Cette molécule possède deux récepteurs : le TNFR1 et le TNFR2. Le TNFR1 est un récepteur exprimé à la surface de toutes les cellules. L’activation de sa voie de signalisation déclenche la mort cellulaire et elle est souvent associée à des phénomènes inflammatoires. Le TNFR2, quant à lui, est exprimé à la surface des cellules immunitaires, des cellules endothéliales et des cellules neuronales. L’activation de la signalisation du TNFR2 conduit à la survie et à la prolifération cellulaire. Le TNFR2 est de plus, associé à des mécanismes anti-inflammatoires. Les lymphocytes T régulateurs (Treg), cellules clé dans le contrôle de la réponse immunitaire, sont caractérisés par l’expression du facteur de transcription Forkhead box P3 (FoxP3) et sont défectueux chez des patients atteints de PR. Ces cellules expriment les deux récepteurs du TNFα et sont capables d’inhiber l’action des cellules inflammatoires et particulièrement des T effecteurs par différents mécanismes d’immunosuppression. Les Treg exprimant le TNFR2 représentent la population la plus immunosuppressive actuellement recensée. L’objectif de notre travail a été de mieux comprendre le rôle des Treg exprimant le TNFR2 dans le contrôle de l’inflammation dépendante du TNFα. Tout d’abord, nous avons montré que la signalisation TNFα-TNFR2 sur les Treg augmentait le maintien de l’expression de FoxP3 ainsi que la prolifération de ces cellules. L’expression du TNFR2 est en outre liée à une stabilité accrue de ces cellules. Ces résultats peuvent expliquer le rôle important que pourraient jouer les Treg TNFR2+ dans le contrôle de l’inflammation dépendante du TNFα. Afin de confirmer cette hypothèse, nous avons démontré, dans deux modèles expérimentaux d’inflammation dépendants du TNFα (arthrite et psoriasis), que les Treg TNFR2+ jouaient un rôle prépondérant dans le contrôle de l’inflammation. Enfin, des expériences effectuées chez des patients atteints de PR ont mis en évidence que les traitements anti-TNFα conduisaient à une augmentation de la fréquence des Treg TNFR2+ circulants chez des patients répondeurs. En démontrant le rôle prépondérant des Treg TNFR2+ dans la résolution de l’inflammation, ce travail ouvre la voie vers l’élaboration de thérapies ciblant le système TNFα/TNFR plus spécifiques pour le traitement de la PR et d’autres pathologies dépendantes du TNFRheumatoid arthritis (RA) is a chronic inflammatory disease with unknown etiology. In this pathology, inflammation is mainly dependent on the pro-inflammatory cytokine TNFα. This molecule acts through two receptors: TNFR1 and TNFR2. TNFR1 is expressed on almost all cell types. Activation of this pathway mainly leads to cell death and is often associated with pro-inflammatory response. In contrast, TNFR2 is expressed on immune, epithelial and neuronal cells. Activation of TNFR2 signaling triggers cellular survival and cell proliferation. Furthermore, TNFR2 pathway is associated with anti-inflammatory mechanisms. Regulatory T cells (Treg) play a pivotal role in the control of inflammation and are defective in RA. They are characterized by the expression of transcriptional factor Forkhead box P3 (FoxP3). Tregs express both TNFα receptors and are able to inhibit inflammatory cells, specifically effector T cells using various immunosuppressive mechanisms. Treg expressing TNFR2 have been identified as the most suppressive Treg population. The aim of this study was to elucidate the role of TNFR2+ Tregs in TNFα mediated - inflammation by. Firstly, we have shown that TNFα-TNFR2 signaling on Tregs increased their proliferation and helped to maintain FoxP3 expression. Moreover, TNFR2 expression was associated with increased Treg stability. These results could explain the potential role of TNFR2+ Tregs in control of TNFα mediated - inflammation. To confirm this hypothesis, we demonstrated, in two models of inflammation mediated by TNFα (arthritis and psoriasis), that TNFR2+ Tregs play a major role in the control of inflammation. Finally, our experiments in RA patients highlighted that anti-TNFα treatments increased circulating TNFR2+ Treg frequency in responder RA patients. By demonstrating the major role of TNFR2+ Tregs in resolution of inflammation, our work paves the way for therapies targeting more specifically TNFα/TNFR system to cure RA and others TNFα - mediated pathologies
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Boschetti, Gilles. "Impact de l'inflammation intestinale sur la dynamique et la fonction des lymphocytes T régulateurs." Thesis, Lyon, 2016. http://www.theses.fr/2016LYSE1009/document.
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Les maladies inflammatoires chroniques de l'intestin (MICI) sont caractérisées par une sécrétion exagérée de cytokines pro-inflammatoires, une hyperactivation des lymphocytes T effecteurs (Teff) et un contrôle insuffisant par les lymphocytes T régulateurs (Treg). Nous avons montré que le traitement par anti-TNFbetas'accompagne d'une augmentation significative des Treg Foxp3+ dans le sang de patients atteints de MICI en poussée. L'infliximab est associé à une potentialisation de leur fonction suppressive. Dans un 2ème travail nous montrons que les Treg sont incapables de prévenir la colite même s'il existe une augmentation du nombre de Treg dans les ganglions mésentériques ainsi qu'une majoration du nombre et de la fonction suppressive ex-vivo des Treg issus du colon inflammatoire. Cet impact fonctionnel positif sur les Treg issus des ganglions mésentériques était sélectif de la sous-population de Treg NRP1- correspondant aux Treg induits. La diminution significative aussi bien in vitro qu'in vivo de la conversion des LT naïfs en Treg en condition inflammatoire contribue probablement à leur incapacité à contenir la colite. Dans un 3ème travail, nous avons étudié la dynamique des LT Th1, Th17 et Treg et des sous-populations de LT CD4+ co-exprimants IL-17/IFNgamma, IL-17/Foxp3 et IFNgamma/Foxp3 chez des patients MICI en rémission clinique suivis tous les 3 mois. Une élévation des LT Foxp3/IL-17 du sang précédait la rechute de la maladie suggérant un rôle potentiel pathogénique de cette sous-population de LT. Ces éléments illustrent les concepts de conversion et plasticité des Treg au cours des MICI mais aussi leur rôle comme cible pour optimiser et développer de nouvelles biothérapiesInflammatory bowel disease (IBD) are characterized by an excessive secretion of pro-inflammatory cytokines, hyperactivation of effector T cells (Teff) and insufficient control by regulatory T cells (Treg). We showed that treatment with anti-TNFbeta is accompanied by a significant increase in Foxp3+ Treg in the blood of patients with IBD. Infliximab is also associated with a potentiation of Treg suppressive function. In a second study, we showed that Treg are unable to completely prevent colitis, even as we have shown a significant increase in the number of Treg in the mesenteric lymph nodes and also an increase in number and the ex-vivo suppressive function of Treg cells from the inflammatory colon. The positive impact of intestinal inflammation on the suppressive function of Treg from the mesenteric lymph nodes was selective in the sub-population of Treg NRP1- majority representing iTreg. The significant decrease both in vitro and in vivo neo-conversion of LT to naïve Treg in inflammatory conditions, contributing to the inability of Treg to contain colitis. In a third study, we systematically studied the dynamics of LT Th1, Th17 and Treg as well as subpopulations of CD4+ T cells that co-express IL-17/IFNgamma, IL-17/Foxp3 and IFNgamma/Foxp3 from a cohort of IBD patients in clinical remission followed every 3 months. A rise in the blood of a Treg Foxp3+ mixed population producing IL-17 preceded the onset of a relapse of IBD suggesting a pathogenic potential of this subpopulation of LT. All these elements illustrate the concepts of conversion and plasticity of Treg in IBD but also the key role of Treg as a target to optimize and develop new biological therapies
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Megat, Salim. "Traitement de la douleur neuropathique : des antidépresseurs aux inhibiteurs de phosphodiestérases." Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ085/document.
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Les antidépresseurs ont un effet antiallodynique qui dépend de la stimulation des récepteurs β2-adrénergiques. Ceux-ci stimulent la production d’adénosine monophosphate cyclique (AMPc) régulé par les phosphodiestérases de type 4 (PDE4). Nous avons ici étudié l’effet d’inhibiteurs de PDE (iPDE) sur la douleur neuropathique, grâce à des approches de pharmacologie comportementale chez la souris complétées par de l’imagerie calcium et des approches moléculaires. Nos résultats montrent un effet antiallodynique des iPDE4 et des iPDE5. L’action des iPDE4 est liée à une diminution d’expression du TNFα dans le ganglion rachidien et au recrutement des récepteurs delta des opioïdes. Celle des iPDE5 nécessite à la fois les récepteurs mu et delta. Nous montrons aussi que l’action d’un iPDE4 dépend de la dose, l’activation de cellules gliales semblant corrélée à l’effet antiallodynique à faible dose, alors que celle des neurones à forte dose a un effet pronociceptif via les récepteurs TRPV1Antidepressants have an antiallodynic action that is dependent on β2-adrenoceptor stimulation. These receptors stimulate the cAMP production, which is regulated by type 4 phosphodiesterases (PDE4). Here, we studied that action of PDE inhibitors (iPDE) on neuropathic pain, using behavioral pharmacology approaches in mice, completed by calcium imaging and molecular approaches. Our results show the iPDE4s and iPDE5s have an antiallodynic action. The iPDE4s act through a decreased expression of TNFα in dorsal root ganglia and the recruitment of the delta opioid receptors. The action of iPDE5 requires both mu and delta opioid receptors. We also show that the action of an iPDE4 depends on the dose, the activation of glial cells at low dose being correlated with an antiallodynic action, while the recruitment of neurons at higher doses has a pronociceptive action via TRPV1 receptors
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Jagielski, Michal Wojciech [Verfasser]. "Einfluss von Interleukin-10 und TNFα auf die chondrogene Differenzierung der humanen mesenchymalen Stammzellen / Michal Wojciech Jagielski." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2015. http://d-nb.info/1075757282/34.
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Besset, Valérie. "Expression et régulation du système IGF par le TGFβ1 et le TNFα dans les cellules somatiques testiculaires." Lyon 1, 1994. http://www.theses.fr/1994LYO1T901.
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Raices, Raquel Marie. "A Novel Role For Il-1 Cytokines And Tnfα In Ifnγ Production, Which Is Mediated By Iκbζ." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1211994580.
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Chaudhry, Daniel [Verfasser], and Florian [Akademischer Betreuer] Krötz. "Die Bedeutung des TNFα-Rezeptors 1 auf die Endothelfunktion nach Ischämie/Reperfusion / Daniel Chaudhry ; Betreuer: Florian Krötz." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2016. http://d-nb.info/1125371528/34.
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Lima, Luana Nepomuceno Gondim Costa. "Estudo do polimorfismo dos genes das citocinas TNFα, IFNγ, TGFβ, IL-6, E IL-10 em hanseníase." reponame:Repositório Institucional da UFC, 2009. http://www.repositorio.ufc.br/handle/riufc/1904.
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LIMA, Luana Nepomuceno Gondim Costa. Estudo do polimorfismo do genes das citocinas TNFa, IFNy, TGFß, IL-6, E IL-10 em hanseníase . 2009. 164 f. Dissertação (Mestrado em Microbiologia Médica) - Universidade Federal do Ceará. Faculdade de Medicina, Fortaleza, 2009.Submitted by denise santos (denise.santos@ufc.br) on 2012-01-05T12:56:35Z No. of bitstreams: 1 2009_dis_lngclima.pdf: 1702836 bytes, checksum: 54a1aa9b42b5683d9013d146e3e741d1 (MD5)
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As citocinas desempenham um papel importante na resposta imune do hospedeiro contra o M. leprae. Polimorfismos de genes de citocinas têm sido implicados como um fator do hospedeiro influenciando a susceptibilidade para doenças infecciosas. O objetivo deste estudo foi verificar a relação entre a hanseníase e os polimorfismos dos genes TNFα (fator de necrose tumoral-α) -308 G→A; IFNγ (interferon-γ) +874 T→A; IL-6 (interleucina-6) -174 G→C; IL-10 -1082 A→T, -819 C→T, -592 A→C e TGFβ (fator de crescmento tumoral-β) códon 10 e códon 25. O estudo foi realizado com moradores do município de Sobral com 15 anos ou mais, no Estado do Ceará, durante o período de março de 2006 a julho de 2008. Os indivíduos foram divididos em três grupos. O grupo caso índice foi composto por 46 indivíduos com hanseníase. Controles internos foram 110 contactantes que residiam no domicílio do caso índice e os controles externos foram 83 indivíduos que não residiam no mesmo domicílio do caso índice. Desses indivíduos foram coletados 3ml para extração de DNA através do “Genomic Prep Blood DNA Isolation Kit” (GE Healthcare) e para tipificação dos polimorfismos dos genes das citocinas através do “kit” da “One-Lambda” (Canoga Park, CA, EUA). Também forma coletados 4,9ml de sangue para detecção de anticorpos IgM para PGL-I utilizando um teste ELISA. Os dados epidemiológicos e clínicos foram obtidos a partir de um questionário aplicado à todos participantes, padronizado para o projeto “Epidemiologia da hanseníase no Ceará: aprofundamento dos estudos imuno-epidemiológicos”, ao qual esse estudo está vinculado. Assim, não foram observadas associações significantes entre os polimorfismos dos genes das citocinas estudados e a susceptibilidade à hanseníase. Em relação ao gene IL-10, os indivíduos com o genótipo GCC/GCC apresentaram uma tendência a desenvolver a hanseníase mais precocemente. Em relação aos SNPs do gene IFNγ e TGFβ encontramos uma associação do genótipo T/T do IFNγ e do genótipo T/T G/G do TGFβ com uma predisposição à doença em indivíduos vacinados, podendo ser que indivíduos com esses genótipo não sejam beneficiados com a vacina. Em relação aos SNPs do gene IL-6 do grupo de controles internos foi observada uma associação entre um considerável aumento do genótipo C/C e a positividade para o anti-PGL-I. Dessa forma, o estudo do polimorfismo dos genes das citocinas traz um melhor esclarecimento da relação entre a genética do hospedeiro e a hanseníase, complementando estudos sobre a sua transmissão e fatores intra e extra-familiares em suas características imunológicas.
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Galenkamp, Koen M. O. "Priming neuroblastoma for cisplatin and etoposide drug therapy: Role of NF-κB in TNFα-induced expression of Fas." Doctoral thesis, Universitat Autònoma de Barcelona, 2015. http://hdl.handle.net/10803/326455.
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El neuroblastoma (NB) es un cáncer pediátrico que representa ~15% de muertes en cánceres infantiles. Los NBs de alto riesgo se caracterizan por una gran heterogeneidad e agresividad, que conlleva un mal pronóstico para el paciente. A pesar de las mejoras alcanzadas con las estrategias estándar en los últimos 20 años, la prevalencia de supervivencia después de cinco años continua por debajo del 50%. Esta situación pone de manifiesto la necesidad del desarrollo de nuevas estrategias para afrontar este problema.
La activación de los receptores de muerte (DR) se ha propuesto como una alternativa a los tratamientos clásicos de quimio- y radio-terapia en distintos tipos de cáncer. En el caso de los NBs, esta aproximación fue descartada por el hecho de que entre un 50 y 70% de ellos no presentan expresión de caspasa-8. A pesar de ello, un grupo significativo de pacientes de NB se podrían beneficiar de un tratamiento que promoviera la muerte a través de la activación de los DR. Se conoce poco de la vía de señalización activada por los DR (especialmente Fas y TNFR1) y de su regulación en NBs, por ello consideramos básico su estudio antes de testar su posible relevancia terapéutica.
Dado a que se ha descrito que la citoquina TNFα induce la expresión de Fas en diferentes tipos de cáncer, nosotros decidimos abordar el co-tratamiento de TNFα con FasL como estrategia terapéutica para el tratamiento de NB.
Para llevar a cabo nuestro estudio, caracterizamos la señalización intracelular y la inducción de muerte a través de TNFR1 y Fas en ocho líneas celulares clínicamente representativas de NB. Observamos que el tratamiento con TNFα induce la expresión de Fas a través de la activación de la vía NF- κB e sensibiliza a la muerte inducida por FasL. A demás, el tratamiento con TNFα promueve la citotoxicidad de agentes genotóxicos, como cisplatino y etoposido, a través de la activación de la caspasa-8. La caracterización más en detalle que realizamos nos llevó a la conclusión que la heterogeneidad presente en neuroblastomas también se hace patente en los niveles de expresión de Fas y en su modulación por TNFα. La sensibilización a la muerte inducida por FasL, cisplatino o etoposido mediada por TNFα solo se podía observar en aquellos NBs donde TNFα era capaz de inducir la expresión de Fas.
En conclusión, nuestros resultados evidencian que TNFα sensibiliza NBs a la muerte inducida por FasL a través de la inducción de la transcripción de FAS mediada por NF- κB. A demás, el pre-tratamiento con TNFα incrementa la muerte inducida por cisplatino y etoposido. Nuestros resultados revelan un nuevo mecanismo que pude mejorar los tratamientos que actualmente se utilizan para la erradicación de los NBs.Neuroblastoma (NB) is a pediatric solid tumor that accounts for ~15% of all cancer-related deaths in infants. High-risk NBs are hallmarked by a high degree of heterogeneity and aggressiveness, which results in poor patient outcome. Despite the improvement of standard therapies in the last twenty years, five-year survival rates are still below 50%, which impels the development of new treatment strategies for this condition. Activation of death receptors (DRs) has been proposed as an alternative to standard chemo- and radio-therapies for various types of cancer. In NB, this approach has been largely disregarded, possibly due to the silencing of caspase-8 in 50-70% of the cases. Nevertheless, a significant group of NB patients could benefit from treatment that induces cell death through DR activation. Characterization of DR signaling (especially Fas and TNFR1) and their regulation in NB has been limitedly studied, but is a prerequisite for assessing their therapeutic relevance. Given that the cytokine TNFα has been described to induce Fas expression in various types of cancer, we addressed whether TNFα and FasL co-treatment could be a valid therapeutic strategy in NB. For the purpose of the study, TNFR1- and Fas-mediated signaling and cell death induction was characterized in a set of eight clinically representative NB cell lines. TNFα treatment was shown to induce Fas expression through NF-κB-mediated transcription of FAS and primed for FasL-induced cell death. Moreover, TNFα treatment enhanced the cytotoxic effects caused by DNA-damaging agents (i.e. cisplatin and etoposide) through caspase-8 activation. Further characterization revealed that the high degree of heterogeneity between NBs is also visible at the levels of Fas expression and modulation thereof by TNFα. TNFα-mediated priming for FasL-, cisplatin-, and etoposide-induced cell death was only observed for NBs that induced TNFα-mediated Fas expression. In conclusion, our findings reveal that TNFα primes NB for FasL-induced cell death through the NF-κB-mediated induction of Fas expression. Moreover, TNFα pre-treatment enhanced cisplatin- and etoposide-induced cell death. These findings unveil a novel mechanism that could improve the efficacy of treatment regimens currently used for the eradication of NB tumors.