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Berg, Arjen van den. "Post-transcriptional modulation of IL-6 and IL-8 responses in structural airway cells." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2006. http://dare.uva.nl/document/32479.
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Mansuy, Adeline. "IL-6 tronquée, un antagoniste naturel de l’IL-6 ? : sélection d’un système d’expression : établissement de preuves de concept in vitro : dans les hémopathies malignes et dans les adénocarcinomes du rein." Thesis, Lyon 1, 2009. http://www.theses.fr/2009LYO10337.
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L'interleukine-6 (IL-6) exerce des propriétés biologiques multiples telles que l'activation des cellules immunocompétentes, l'activation de la réponse inflammatoire et l'hématopoïèse. Produite également par les cellules tumorales, l'IL-6 impacte la prolifération, la différenciation et la survie de ces dernières. L'IL-6 représente donc depuis plusieurs années une cible thérapeutique pertinente. Dans la première partie de ce travail, nous avons exploré une nouvelle piste potentielle pour bloquer l'activité biologique de l'IL-6, en utilisant un antagoniste naturel que notre équipe a identifié dans plusieurs lignées d'adénocarcinomes du rein, à savoir la molécule tronquée tIL-6. Suite à l'évaluation comparée de deux systèmes d'expression (E. coli versus CHO), nous avons retenu les cellules CHO comme source de production de fractions enrichies en tIL-6 par chromatographie de gel d'exclusion. Disposant d'un panel d'adénocarcinomes de rein (ACHN, Caki1, CLB CHA, CLB VER) et d'une lignée érythroleucémique (TF1), l'activité fonctionnelle de tIL-6 in vitro a été étudiée sur (1) la signalisation IL-6 induite, (2) la prolifération cellulaire IL-6 induite, la survie cellulaire et (4) la modulation de l'expression de protéines relevantes de l'apoptose. La molécule tIL-6 bloque la phosphorylation de la tyrosine Tyr705 de STAT3, qui est un des éléments clés de la voie de signalisation de l'IL-6. Nous rapportons également une autre observation nouvelle indiquant que tIL-6 exerce un effet pro-apoptotique sur certaines lignées RCC. Dans la seconde partie de notre étude, l'impact d'un Ac Mo anti IL-6 dans la réversion de la résistance aux cytotoxiques ou à la radiothérapie a été étudié. Nos résultats démontrent que la voie IL-6 ne constituerait pas un mécanisme majeur de résistance<br>Interleukin-6 (IL-6) plays numerous physiological roles including haematopoiesis, immune response and inflammation, but also plays a role in modulating cell growth, differentiation and survival of tumors cells. The first goal of the present study was to investigate on the potential role of the truncated protein IL-6 (tIL-6) encoded by the spliced IL-6 mRNA discovered in renal carcinoma cells (RCC). The R&D program was designed based on an industrial approach, aiming at reaching the decision stage to enter or not into preclinical development. Firstly two different expression systems were investigated (E. coli versus CHO cell line). The mammalian expression system was selected as the protein source since a recombinant glycosylated tIL-6 with a molecular weight similar to the predicted natural molecule was obtained from enriched fractions following size exclusion chromatography. Secondly by using a cell line panel including renal carcinoma cells (ACHN, Caki-1, CLB CHA, CLB-VER ) and an erythroleucemic cell line (TF1), in vitro tIL-6 functional activity were analyzed on (1) IL-6 induced signaling, (2) IL-6 induced cell proliferation, (3) on cell survival and also (4) on expression of specific set of proteins involved in apoptosis pathways. The truncated IL-6 was found inhibit IL-6 induced STAT3 Tyr705 and to induce apoptosis in some RCC cell lines which could be depending on IL-6 expression. Understanding more precisely the role of natural truncated IL-6 and its impact in cell tumour growth control will be a major issue in the development of innovative approach to antagonize directly or not IL6. The second goal of the present study was to investigate on reversing resistance of cancer cell lines to cytotoxics or ionizing radiations through the use of a monoclonal antibody directed against IL-6. Our data support the fact that IL-6 is not the preponderant actor of cell resistance to cytotoxics and ionizing radiations, which seems to be regulated by a complex network of proteins
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Oquendo, Mora Jenny. "Effet du virus de l'hepatite b sur l'expression des genes des cytokines (il-1, il-6, tnf, il-10) in vitro par des lignees mono-lymphocytaires humaines : (thp-1, h9, namalwa)." Paris 11, 1996. http://www.theses.fr/1996PA11T018.
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Vincent, Thierry. "Recherche de gènes induits par l'interleukine-6 (IL-6) dans des cellules plasmocytaires malignes humaines : induction et fonction du CD44." Montpellier 1, 1999. http://www.theses.fr/1999MON11096.
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Martineau-Costes, Valérie. "Cytokines de la famille IL-6 et syndecan-1 dans le myélome multiple et le cancer du rein." Montpellier 1, 1998. http://www.theses.fr/1998MON1T015.
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Alberti, Laurent. "Interleukine 6 et prolifération de l'adénocarcinome du rein : clonage et caractérisation d'une IL-6 tronquée produite par les lignées d'adénocarcinome du rein." Lyon 1, 2002. http://www.theses.fr/2002LYO10187.
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L'adénocarcinome du rein est la septième cause de mortalité par le cancer en France. 25 à 50% des patients présenteront des métastases avec une survie globale à cinq ans de 5%. L'adénocarcinome du rein produit une grande variété de facteurs de croissance et de cytokines contrôlant la prolifération et la dissémination des cellules tumorales, en interagissant entre elles de manière additive, synergique ou antagoniste. Les travaux antérieurs de notre équipe ont montré le rôle central de l'interleukine 6 dans la physiopathologie de cette affection, comme facteur endocrine proinflammatoire et paracrine immunosuppresseur. Au cours de ce travail de thèse nous avons montré : 1) que l'IL-6 agissait comme facteur de croissance intacrine dans toutes les lignées tumorales d'adénocarcinome du rein étudiées ; 2) que la prolifération des lignées d'adénocarcinome du rein est inhibée par un oligonucléotide antisens dirigé contre le deuxième exon de l'ARNm de l'IL-6 ; 3) que l'IL-4 et IL-13 agissent de manière additive avec l'antisens ; 4) que les lignées d'adénocarcinome du rein produisent un inhibiteur naturel de l'IL-6 traduit à partir d'un ARNm de l'IL-6 dans lequel l'exon 2 est épissé. La production in vitro et l'analyse des propriétés biologiques de cet inhibiteur ont été l'objet de ce travail de thèse. Cet inhibiteur bloque l'activité mitogène de l'IL-6 sur la lignée de myélome U266, sur la lignée CLB-TUG, et s'oppose à l'inhibition de la différenciation des progéniteurs CD34+ en cellules dendritiques induites par l'IL-6<br>The renal carcinoma is the seventh cause of cancer mortality in France. 25 to 50% of the patients will present metastases with 5% of a survival rate at five years. The tumoral cell produces a large variety of cytokines and growth factor controlling tumor proliferation and dissemination. Former work of our team showed the central role of interleukin 6 (IL-6) in the physiopathology of this affection, like endocrine factor in proinflammatoire syndrome and paracrine in immunosuppressor. During this thesis work, we showed that : 1) IL-6 like growth factor promoter intacrine in all of RCC cell line, 2) the proliferation of the RCC cell line is inhibited by an oligonucleotide antisens directed against the second exon of IL-6 mRNA, 3) IL-4 and IL-13 act in an additive way with antisens, 4) RCC cell lines produce a natural inhibitor (tIL-6) resulting of spliced exon 2 of IL-6 mRNA. This inhibitor blocks IL-6 mitogene activity on the myeloma U266, on the RCC cell line (CLB-TUG) and stop the inhibition of the differentiation of CD34+ progenitor in dendritic cells induced by IL-6
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Gaillard, Jean-Philippe. "Etude structurale et fonctionnelle du récepteur de l'interleukine-6 : interactions moléculaires dans la médiation du message IL-6." Montpellier 2, 1994. http://www.theses.fr/1994MON20275.
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L'interleukine-6 (il-6) est une cytokine multifonctionnelle qui est impliquee comme facteur de croissance dans les proliferations plasmocytaires benignes et malignes. Sa neutralisation a l'aide d'anticorps monoclonaux anti-il-6, entraine le bloquage du clone tumoral chez des patients atteints de myelome multiple (mm). Dans le but d'explorer la possibilite de bloquer le message il-6 en ciblant son recepteur, nous avons produit sept anticorps monoclonaux specifiques de la chaine gp80 du recepteur de l'interleukine-6 (il-6r). Nous avons recherche la fonction des epitopes cibles par nos anticorps. Les etudes d'inhibition des interactions ligand/recepteur et l'inhibition de la proliferation de lignees dependantes de l'il-6 nous ont montre que deux epitopes sont impliques dans la fixation de la cytokine et qu'un troisieme epitope est implique dans l'interaction des deux chaines du recepteur. L'association d'anticorps de specificite differente conduit a une inhibition drastique de la signalisation par l'il-6. Le dosage de la forme soluble du recepteur (sil-6r) nous a montre l'existence de concentrations circulantes elevees (1nm) et une augmentation significative dans les gammapathies monoclonales. L'amplitude de l'expression du sil-6r est donc un excellent element de diagnostic et un des meilleurs facteurs de pronostic dans le mm. Nous avons confirme l'activite agoniste de cette forme soluble dans la signalisation par l'il-6. En outre, les resultats obtenus nous ont permis de presenter une estimation de l'affinite de la gp130 pour le complexe soluble il-6/sil-6r. Les travaux en cours, visent a definir la place du sil-6r par rapport a l'il-6r membranaire dans la mediation du message il-6. Du fait de sa concentration physiologique elevee et de son activite biologique, cette molecule est susceptible d'etre une cible privilegiee de therapeutique anti-il-6
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Porée, Benoît. "Effets de l'interleukine-6 (IL-6), de son récepteur soluble (sIL-6R) et du facteur de transcription Erg sur l'expression du collagène de type II dans des chondrocytes articulaires." Caen, 2007. http://www.theses.fr/2007CAEN2060.
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Le collagène de type II est un homotrimère de chaînes α1(II) codées par le gène COL2A1. La synthèse de ce marqueur phénotypique du cartilage est fortement altérée lors de l'arthrose. L'IL-6 est une cytokine proinflammatoire nécessitant la coopération du récepteur soluble sIL-6R pour exercer ses effets. Ce mécanisme pallie l'absence totale ou partielle du récepteur membranaire IL-6R dans certains types cellulaires, dont les chondrocytes. Notre étude démontre que l'IL-6 et/ou sIL-6R inhibent la transcription du gène COL2A1 via une région promotrice comprise entre -63 et -35 pb. Cette inhibition met en jeu les facteurs de transcription Sp1 et Sp3 dont l'activité de liaison au niveau du site -41/-33 pb est réduite sous l'action du duo cytokinique. Par ailleurs, la cytokine et/ou son récepteur soluble diminuent le ratio Sp1/Sp3. L'inhibition fonctionnelle de Sp1 et/ou Sp3, par des leurres oligonucléotidiques ou siRNA, abolit les effets délétères de l'IL-6 et/ou sIL-6R sur la transcription du gène COL2A1, suggérant l'implication d'un complexe hétérotypique Sp1/Sp3 dans le mécanisme réactionnel régi par le complexe IL-6/sIL-6R. De plus, il apparaît que les histones désacétylases puissent intervenir dans ce processus, comme l'atteste les expériences utilisant la trichostatine A, ainsi que les co-immunoprécipitations démontrant une interaction physique entre Sp1 et HDAC1. Dans une seconde partie, nous nous sommes intéressés au facteur de transcription Erg. Ce dernier appartient à la famille des protéines ETS et apparaît indispensable à la mise en place du cartilage articulaire lors de l'embryogenèse. Nous montrons ainsi que des surexpressions de ce facteur dans des chondrocytes articulaires de lapin, augmentent la production du collagène de type II via un contrôle transcriptionnel. Cette stimulation s'exerce au niveau d'une région de l'amplificateur intronique comprise entre +2 127 et +2 384 pb. Au contraire, des surexpressions d'une protéine Erg tronquée, restreinte au domaine de liaison ETS, n'exercent aucun effet sur l'activité transcriptionnelle de COL2A1. En revanche, elle entre en compétition avec la protéine complète et annule ses effets stimulateurs. Le facteur Erg stimule également les expressions de Sp1, Sp3 et Sox9, suggérant que ces facteurs puissent intervenir dans la stimulation exercée par Erg<br>Type II collagen is composed of α1(II) chains encoded by the COL2A1 gene. Alteration of this cartilage marker is a common feature of osteoarthritis. IL-6, a pro-inflammatory cytokine, needs to exert its effects in some cases, a soluble form of receptor, sIL-6R, which exerts agonistic action. This mechanism can make up for the partial or total absence of membrane anchored IL-6 receptors in some cell types, such as chondrocytes. Our study shows that IL-6 and/or sIL-6R inhibit COL2A1 gene transcription by a -63/-35 sequence. This inhibition implies Sp1 and Sp3 transcription factors whose DNA-binding activity is decreased to the -41/-33 bp site by both IL-6 and sIL-6R. Knock-down of Sp1/Sp3 by siRNA and decoy strategies were found to prevent the IL-6 and/or sIL-6R induced inhibition of COL2A1 transcription, indicating that a heterotypic Sp1/Sp3 complex is required for down-regulation of the target gene. Additionally, experiments using trichostatin A demonstrate that HDAC activity is involved in this inhibitory process, and Sp1 was shown to interact with HDAC1. In a second part, we investigated the effects of Erg that belongs to the ETS family of transcription factors and that plays a key role in cartilage formation. Indeed, we show that overexpression of Erg in rabbit articular chondrocytes, increase type II collagen production through a transcriptional control. This factor up-regulates COL2A1 gene transcription by a first intron sequence localised between + 2 127 and + 2 384 bp. On the contrary, overexpression of a dominant-negative protein restricted to the ETS domain dn-Erg, shows no effect on the COL2A1 transcriptional activity. On the other hand, dn-Erg enters in competition with the native protein and abrogates its stimulating effects. Erg also stimulates Sp1, Sp3 and Sox9 expressions, suggesting that these factors can be involved in Erg induced stimulation of COL2A1
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Szabo-Fresnais, Nicolas. "Dialogues entre les voies de signalisation de l'AMPc et celles de l'IL-1 dans la régulation de l'expression de l'IL-6 et rôle de l'IL-6 dans les thyrocytes et dans les cardiomyocytes." Phd thesis, Université Paris Sud - Paris XI, 2009. http://tel.archives-ouvertes.fr/tel-00451370.
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L'interleukine-6 (IL-6) est une cytokine associée aux maladies auto-immunes de la glande thyroïde et qui pourrait aussi avoir un rôle dans le développement de l'hypertrophie cardiaque pathologique. Dans les cellules thyroïdiennes FRTL-5 et dans les cardiomyocytes de rats adultes, nous montrons que la sécrétion et l'expression de l'ARNm de l'IL-6, stimulées par l'interleukine-1 (IL-1), sont augmentées de manière synergique par la voie de l'AMPc/PKA. Dans les cellules FRTL-5, cet effet synergique s'exerce aussi au niveau de l'activation du promoteur de l'IL-6 et implique les sites AP-1 et CRE ainsi que les facteurs de transcription c-Fos et Fra2. L'IL-6 et son récepteur membranaire stimulent les voies de signalisation impliquant STAT3 et ERK-5 dans les cellules FRTL-5. Dans les cardiomyocytes, STAT3 est activé par l'IL-6 uniquement en présence de son récepteur soluble. Nous montrons que ce mécanisme de conduit à la stimulation de marqueurs associés au processus hypertrophique pathologique.
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Guillot, Xavier. "Effets thérapeutiques et anti-inflammatoires de la cryothérapie dans les rhumatismes inflammatoires." Thesis, Besançon, 2016. http://www.theses.fr/2016BESA3009/document.
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La cryothérapie est utilisée de manière large et empirique à visée adjuvante dans les rhumatismes inflammatoires, avec un niveau de preuve faible. Dans une revue systématique de la littérature, en poolant les données de 6 études non contrôlées, nous avons pu démontrer que la cryothérapie (locale ou corps entier) appliquée deux fois par jour pendant 7 à 15 jours réduisait significativement l'EVA douleur et le score d'activité DAS25 dans la polyarthrite rhumatoïde. La cryothérapie locale (glace ou gaz froide) montrait par ailleurs des effets taille intra-classes supérieurs à ceux obtenus en utilisant la cryothérapie corps entier. L'objectif de ce travail était de mesurer les effets de la cryothérapie locale sur al douleur, l'inflammation synoviale et systémique chez les patients arthritiques et dans le modèle murin d'arthrite à l'adjuvant. Dans les études randomisées CDRI et ALGGAR, nous avons évalué les effets de deux applications locales de froid (glace versus gaz froid) sur la douleur, l'activité Doppler et les taux protéiques de cytokines intra-articulaires controlatéraux non souffrant d'arthrites de genou non septiques. Les genoux arthritiques controlatéraux non traités étaient utilisés comme contrôles. Nous avons par ailleurs étudié in vitro les effets de l'hypothermie modérée (30°C pendant 2heures) sur l'expression protéique des cytokines dans un modèle de culture de rotules de rats arthritiques. Nous avons enfin étudié in vitro dans l'arthrite à l'adjuvant les effets de l'application sub-chronique de glace ou de gaz froid (2 fois par jour pendant 14 jours versus contrôles arthritiques non traités) sur le score d'arthrite, le diamètre de cheville, la transcription des gènes codant pour les cytokines pro-inflammatoires dans les pattes arrières (Q-RT-PCR) et l'expression protéique des cytokines dans le plasma (Multiplex et ELISA) après 14 jours de traitement. Dans l'étude CDRI, la cryothérapie locale (glace et gaz froid) réduisait significativement l'EVA douleur ainsi que le score Doppler dans les genoux traités, ces effets persistant le lendemain des deux applications. Dans une analyse intermédiaire des résultats de l'étude ALGGAR, en combinant les deux groupes de traitement (glace et gaz de froid), nous avons observé une baisse des taux d'IL-6, d'IL-1β et de VEGF dans le liquide articulaire arès deux applications. dans les cultures d'explants de rotules de rats arthritiques, l'hypothermie ponctuelle réduisait significativement les taux d'IL-6, IL-17A et IL-1β dans les pattes arrières après 14 jours de traitement. Les deux modalités réduisaient significativement les niveaux plasmatiques d'IL-17A et la glace réduisait en outre les taux d'IL-6 et de VEGF. Nous n'avons observé aucun effet de la cryothérapie locale sur le voie du TNF-α chez l'homme ni chez l'animal. Nos résultats démontrent pour la première fois un effet thérapeutique et anti-inflammatoire de la cryothérapie locale dans l'arthrite. Les effets biologiques était IL-6/IL-147 dépendants et TNF-α indépendants. Des études complémentaires permettront de mieux caractériser les mécanismes moléculaires sous-jacents et de déterminer su la cryothérapie locale pourrait être une alternative aux AINS et corticoïdes dans les rhumatismes inflammatoires<br>Cryotheapy i widely and empirically used in an adjuvant setting in inflammatory rheumatic diseases, with a low level of evidence. We performed a systematic review of the literature and, by pooling data from 6 non-controlled studies, we could show that local cryotherapy (local or whole-body cryotherapy) applaied twice a day for 7-15 days significantly reduced the pain VAS and the DAS28 activity score in rheumatoid arthritis. Furthermore, local cryotherapy (ice packs or cold gas) showed significantly greater intra)class effect-sizes compared to whole-body cryotherapy. The aim of this work was to measure the effects of local cryotherapy on pain, synovial and systemic inflammation in arthrici patients and in the murine model of adjuvant-induced arthritis. First, in the CDRI and ALGGAR randomized studies, we evaluated the effects of 2 local cold applications (ice versus cold gas) on pain, power Doppler activity and intra-joint cytokine protein levels in 46 patients suffering from non-septic knee arthritides. Contralateral arthritic knee were used as control. Secondly, we studied the in vitro effects of mild hypothermia (30°C for 2 hours) on cytokine protein expression in a model of cultured arthritic rat patellae. Thidly, we studied the in vitro effects of sub-chronically applied ice or cold gas (twice a day for 14 days versus non-treated arthritic controls) on the arthritis score, the ankle diameter, pro-inflammatory cytokine gene transcription levelsin hind paws (Q-RT-PCR) and cytokine plasma protein levelx (Multiplex and ELISA) after 14 days of treatment. In the CDRI study, local cryotherapy (ice and cold gas) significantly reduced the pain VAS and the power Doppler score in treated kness, and these effects remained significant the day afetr 2 cold applicaitions. In an intermediate analysis of the ALGGAR study results, by pooling the 2 treatment groups, we could show significant decreases in IL-6 protein, IL-1β and VEGF synovial fluid protein levels after 2 cold applicatios. In arthritic rat patella explangt culture experiments, punctual hypothermia significantly reduced IL-6 protein levels. In vivon ice was more efficient on the clinical parameters and better tolerated compared to cold gas. Both techniques significantly reduced IL-6, IL-17A ans IL-1β gene transcription levels in hind paws after 14 days of treatment. Both techniques redcued IL-17A plasma protein levles, while ice also reduced IL-6 and VEGF plasma protein levels. Conversely, we observed no effect of local cryotherapy on the TNF-α pathway, neither in patients nor in our animal model. Here we demonstrate for the first time therapeutic and anti-inflammatory effet-cts of local cryothepary in arthritis. The biological effects were IL-6/IL-17-driven and TNF-α independent. Further studies will help elucidate the underlying molecular mlechanisms involved and detemrine whether local cryotherapy might be a safer alternative to NSAIDs ans corticosteroids in inflammatory rheumatic diseases
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Poenaru-Bernard, Oana. "Cytokines de la résorption et marqueurs du rémodelage dans le suivi thérapeutique de pathologies métaboliques osseuses." Paris 7, 2002. http://www.theses.fr/2002PA077154.
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Bouezzedine, Fidaa. "Analyse de l'entrée du virus de l'hépatite B : Etude du processus de fusion et de l'effet de l'interleukine 6." Thesis, Rennes 1, 2015. http://www.theses.fr/2015REN1B003/document.
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L’hépatite B est une maladie infectieuse grave et extrêmement contagieuse. Malgré l’existence d’un vaccin efficace plus de 240 millions de personnes souffrent d’une infection hépatique chronique et plus de 780 000 personnes meurent chaque année des conséquences aiguës ou chroniques de l’hépatite B. Les traitements actuels qui consistent en l’utilisation d’interféron et/ou d’inhibiteurs de la réplication virale sont encore insuffisants. De nouvelles thérapeutiques ciblant l’entrée virale sont en développement, notamment le Myrcludex B qui inhibe l’infection en empêchant l’entrée virale. Cependant, les mécanismes d’entrée du VHB dans l’hépatocyte sont encore mal connus. Récemment, l’identification du NTCP comme récepteur spécifique du VHB a permis de mieux comprendre le mécanisme d’attachement de ce virus. Ce récepteur constitue une nouvelle cible pour des antiviraux. C’est aussi un transporteur de sels biliaires fortement régulé par les cytokines pro-inflammatoires. Les objectifs de ce travail étaient : (i) d’étudier la fusion du VHB, étape cruciale de l’entrée d’un virus enveloppé, en établissant un modèle artificiel de fusion entre des particules virales purifiées et des liposomes, et (ii) d’étudier l’effet de l’interleukine 6 sur l’entrée virale. Nous n’avons pas pu mettre en évidence de fusion entre les particules virales et des liposomes suggérant l’incapacité de ce virus à fusionner avec une bicouche lipidique néanmoins il reste possible que des conditions particulières liées aux spécificités du VHB soient requises. Nos résultats ont également montré que l’interleukine 6 inhibait l’entrée virale en diminuant l’expression de NTCP<br>Hepatitis B is a severe and extremely contagious infectious disease. Despite an effective vaccine more than 240 million people are suffering from chronic infection and over 780 000 persons die each year from the consequences of acute and chronic hepatitis B. Current treatments consisting in the use of interferon and/or viral replication inhibitors are insufficient. New therapeutics targeting viral entry are in progress, such as Myrcludex B that has been shown to inhibit HBV infection by preventing HBV entry. However, the mechanism of HBV entry into hepatocytes is still poorly understood. Recently, the identification of NTCP as a specific HBV receptor allowed us to better understand the attachment of this virus. This receptor is now a target for antiviral molecules. It is also a carrier for bile salts known to be strongly regulated by pro inflammatory cytokines. The aims of our thesis were: (i) to study HBV entry by establishing an artificial model of fusion between purified viral particles and liposomes, and (ii) to study the interleukin 6 effect on viral entry. Our results with fusion assays suggest an absence of fusion in the entry process of this virus. However, fusion could require peculiar conditions related to HBV specificities. Our results also demonstrated that interleukin 6 inhibits virus entry by down-regulating NTCP expression
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Perrier, Julie. "Criblage virtuel et expérimental de chimiothèques pour le développement d’inhibiteurs des cytokines TNF-alpha et IL-6." Thesis, Paris, CNAM, 2014. http://www.theses.fr/2015CNAM0978.
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Les biothérapies (anticorps monoclonaux, récepteurs solubles) ciblant les cytokines IL-6 etTNF-alpha pour le traitement des maladies inflammatoires chroniques ont constitué un succèsmajeur de l’industrie pharmaceutique. Elles présentent néanmoins des inconvénientsimportants : résistances, mode d’administration contraignant, coût élevé.Notre équipe travaille sur l’identification de petites molécules inhibant directement cescytokines, afin d’élargir l’offre thérapeutique existante. Administrées par voie orale, ellesconstitueraient une alternative particluièrement favorable aux patients.Durant ma thèse, j’ai réalisé le criblage expérimental (tests cellulaires et tests biochimiquesde liaison) des meilleurs composés identifiés par criblage virtuel d’un grande chimiothèque dediversité, ainsi que de composés dérivés de pyridazine issus d’une chimiothèque médicinale. J’aiainsi pu identifier plusieurs inhibiteurs directs du TNF-alpha et de l’IL-6. De plus, mon travail apermis d’affiner les procédures de criblage du Laboratoire.Ces travaux ouvrent de nouvelles pistes pour le développement de médicaments anti-cytokines<br>Anti-cytokine biologics (monoclonal antibodies, soluble receptors) targeting TNF-alpha and IL-6in chronic inflammatory diseases have been a major success for pharmaceutical industry.However, they exhibit several drawbacks : resistance, difficult administration, high costs.Our team works on the discovery of small molecule inhibitors of cytokines suck as TNF-alphaand IL-6, in order to widen the range of therapeutic drugs. Orally active drugs would represent ahighly beneficial alternative for patients.During my PhD, I have performed an experimental screening (using cellular and biochemicalbinding testings) of the best compounds identified through virtual screening of a large chemicallibrary, and on pyridazine compounds of a medicinal chemical library. I have been able toidentify several small molecules inhibiting the interaction of TNF-! and IL-6 with their receptor.Moreover, my work will have an impact on the laboratory screening strategies.Overall, this work opens new avenues for anti-cytokine drug discovery
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Debuisson, Delphine. "Rétrocontrôle des réponses Th2 par l'interleukine-6 et identification d'un nouveau facteur de transcription exprimé par les lymphocytes T helper folliculaires." Doctoral thesis, Universite Libre de Bruxelles, 2014. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209158.
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L’objectif de notre travail a été de caractériser le rôle de l’IL-6 dans la différenciation des lymphocytes Tfh et des lymphocytes Th2. Les lymphocytes Tfh ont pour fonction d’aider les lymphocytes B à produire des anticorps indispensables pour nous protéger contre divers pathogènes. Les lymphocytes Th2, quant à eux, sont spécialisés dans l’élimination de parasites extracellulaires tels que les helminthes.<p>Dans un premier temps, nous avons voulu identifier les gènes dont l’expression est induite par l’IL-6, avec comme objectif une meilleure compréhension des mécanismes permettant aux lymphocytes T de se différencier en cellules Tfh.<p>Au cours de notre travail, nous avons identifié le facteur de transcription, MyoR (Myogenic Repressor) comme étant exprimé au sein des lymphocytes T helper et dont l’expression est induite par l’IL-6. Nos observations expérimentales ont démontré que le facteur MyoR n’est pas indispensable pour la différenciation des lymphocytes Tfh, ni pour leur fonction. Cependant, l’expression de l’ARNm codant pour MyoR pourrait être utilisée comme un biomarqueur des cellules Tfh in vitro ou in vivo.<p>Nous avons ensuite caractérisé la réponse immune induite in vivo par des cellules présentatrices d’antigènes issues de souris déficientes pour l’IL-6. Cette approche nous a permis de mettre en évidence le rôle immunosuppresseur de l’IL-6 sur le développement des réponses de type Th2. En effet, nous avons montré que l’injection de BMDCs (Bone Marrow derived dendritic cells) IL-6-/- dans des souris receveuses de type sauvage induisent une réponse Th2 augmentée in vivo.<p>Nos résultats suggèrent que l’inhibition de la réponse Th2 par l’IL-6 in vivo et in vitro pourrait impliquer la présence d’un ou de plusieurs miRNAs.<p>Cette inhibition pourrait être un mécanisme de rétrocontrôle afin d’éviter une exacerbation de la réponse immune Th2.<br>Doctorat en Sciences<br>info:eu-repo/semantics/nonPublished
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Bouaouiche, Sarra. "Etude mécanistique des propriétés anti-tumorales du glycéryl trinitrate (gtn) : impact du monoxyde d'azote dans des voies de signalisation induites par des cytokines pro-inflammatoires et dans la régulation de marqueurs de résistance." Thesis, Bourgogne Franche-Comté, 2018. http://www.theses.fr/2018UBFCI010.
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Une des difficultés majeures dans le traitement des cancers est l’acquisition de résistance par les cellules tumorales vis-à-vis de la mort induite par les différentes chimiothérapies. Au sein du laboratoire, nous nous intéressons aux propriétés anti-tumorales d’un donneur de monoxyde d’azote (NO), le Glycéryl TriNitrate (GTN), fréquemment utilisé dans le traitement de l’angine de poitrine. Au cours de ce travail, nous avons étudié les mécanismes moléculaires par lesquels le GTN sensibilise les cellules tumorales de plusieurs types de cancer (colique, mammaire, prostatique) à la mort impliquant des voies de signalisation régulées par des cytokines telles que le TNFα, l’IL-6 ou encore le GDF-15.Une meilleure compréhension des mécanismes sous-jacents à l’action anti-tumorale du GTN permettrait de potentialiser son utilisation comme nouvelle thérapie anti-cancéreuse.Modèle colique : le GTN, en présence de la cytokine pro-inflammatoire TNFα, sensibilise les cellules cancéreuses coliques et mammaires à l’apoptose. Du point de vue mécanistique, le GTN induit la S-nitrosylation de cIAP1, inhibant ainsi son activité ubiquitine E3 ligase. Ce qui abroge la voie de signalisation classique NF-кB de survie cellulaire activée par la voie TNFα/TNFR1 en faveur d’une voie de signalisation pro-apoptotique.Modèle mammaire : le GTN intervient au niveau de la migration cellulaire en altérant la voie de signalisation Jak2/STAT3 activée par la cytokine pro-inflammatoire IL-6, dans un modèle de cancer du sein triple négatif. En présence de dérivés du platine (carboplatine) générant de l’IL-6, le GTN freine la migration des cellules en induisant la S-nitrosylation, et probablement l’inactivation, de la kinase Jak-2, indispensable pour l’activation de la voie.Modèle prostatique : le GTN sensibilise à la mort les cellules cancéreuses prostatiques résistantes au docétaxel en modulant le taux de deux marqueurs de résistance à cette chimiothérapie : la clusterine (CLU) et le growth differentiation factor 15 (GDF-15). Au niveau moléculaire, le GTN diminue le taux de l'isoforme cytoprotectrice soluble de la CLU (sCLU) et augmente le taux de l'isoforme cytotoxique nucléaire (nCLU) dans les cellules prostatiques résistantes au docétaxel. Plus particulièrement, en présence de GTN, nous avons établi un lien entre le GDF-15 et la modulation du taux des isoformes de la CLU<br>One of the main difficulties in the treatment of cancers is the acquisition of resistance by the tumor cells vis-à-vis the death induced by the different chemotherapies. In the laboratory, we are interested in the anti-tumor properties of a nitric oxide (NO) donor, Glyceryl TriNitrate (GTN), frequently used in the treatment of angina pectoris. In this work, we investigated the molecular mechanisms by which GTN sensitizes tumor cells of several types of cancer (colonic, mammary, prostate) to death involving signaling pathways regulated by cytokines such as TNFα, IL-6 or GDF-15.A better understanding of the mechanisms underlying the GTN's anti-tumor action would make it possible to use it as a new anti-cancer therapy.Colon model: GTN, in the presence of the pro-inflammatory cytokine TNFα, sensitizes colon and mammary cancer cells to apoptosis. From a mechanistic point of view, GTN induces S-nitrosylation of cIAP1, thus inhibiting its ubiquitin E3 ligase activity. This abrogates the classical NF-κB signaling pathway of TNFα / TNFR1 activated cell survival in favor of a pro-apoptotic signaling pathway.Mammary model: GTN intervenes at the level of cell migration by altering the Jak2 / STAT3 signaling pathway activated by the pro-inflammatory cytokine IL-6, in a model of triple negative breast cancer. In the presence of platinum (carboplatin) derivatives generating IL-6, GTN inhibits cell migration by inducing S-nitrosylation, and probably inactivation, of Jak-2 kinase, essential for the activation of the way.Prostate model: GTN sensitizes prostatic prostate cancer cells to death by modulating the level of two markers of resistance to this chemotherapy: clusterin (CLU) and growth differentiation factor 15 (GDF-15). At the molecular level, GTN decreases the level of the soluble cytoprotective isoform of CLU (sCLU) and increases the level of nuclear cytotoxic isoform (nCLU) in prostatic cells resistant to docetaxel. More particularly, in the presence of GTN, we have established a link between GDF-15 and the modulation of the isoform rate of the CLU
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Payette, Caroline. "Étude des variations plasmatiques postprandiales des marqueurs inflammatoires IL-6, TNF-α et CRP chez les hommes et les femmes". Master's thesis, Université Laval, 2007. http://hdl.handle.net/20.500.11794/19150.
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Asmane, Irène. "Coopération privilégiée entre le microenvironnement stromal et les variants autonomes du récepteur des androgènes dans le cancer de la prostate." Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAJ032/document.
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Malgré le rôle des variants constitutivement actifs du récepteur des androgènes (RA) et du stroma tumoral dans le cancer de la prostate résistant à la castration (CRPC), leurs relations restent inconnues. Nous rapportons l’impact de l’interleukine-6 (IL-6) sécrétée par les cellules stromales prostatiques (PrSC) sur les cellules épithéliales tumorales prostatiques exprimant les variants autonomes du RA. Le milieu de culture conditionné par les PrSC (CMPrSC) contenait des taux élevés d’IL-6 et induisait une augmentation de l’activité transcriptionnelle de STAT3 dans les LNCaP et C4-2b exprimant le variant RAQ640X, via une activation de pY705-STAT3. Cette activité de STAT3 était inhibée par la neutralisation de l’IL-6. L’analyse par mRNA array et RT-qPCR a mis en évidence un profil transcriptomique spécifique lié à l’expression du RAQ640X et à l’exposition au CMPrSC, impliquant les fonctions de motilité, d’invasion et de migration cellulaires, et l’expression de gènes favorisant la dissémination métastatique. Ainsi, nos résultats illustrent une coopération épithélio-stromale «privilégiée» en présence de variants autonomes du RA, impliquée dans la progression tumorale<br>Constitutively active androgen receptor (AR) variants and stromal microenvironment are involved in castration resistant prostate cancer (CRPC), but their relationship remains unknown. We describe the effects of interleukin-6 (IL6) secreted from prostate stromal fibroblast cells (PrSC) towards prostate epithelial cancer cells expressing constitutively active AR variants. Conditioned culture medium from PrSC (CMPrSC) contained high levels of IL-6 and led to an increased STAT3 transcriptional activity in LNCaP and C4-2b cells expressing the ARQ640X variant, through pY705-STAT3 activation. This STAT3 activity was significantly diminished with neutralizing antibody anti-IL6. Gene expression analysis using mRNA array and RT-qPCR highlighted a specific transcriptional profile related to ARQ640X expression and PrSC exposure, resulting in cellular motility, invasion and cellular migration, and IL-6 genes expression promoting metastatic dissemination. Overall, our data emphasize a “preferred” epithelio-stromal cooperation when expressing constitutive active RA variants, which contributes to tumor progression
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Schebesta, Kathrin [Verfasser]. "Das Endothel sezerniert Interleukin-6 (IL-6) und stimuliert die adrenale Interleukin-6 und Aldosteronsynthese über einen Interleukin-6 unabhängigen Mechanismus / Kathrin Schebesta." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2015. http://d-nb.info/1079652612/34.
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Terrades, Garcia Nekane. "Interleukin-6 (IL-6)/IL-6 receptor and persistence of inflammation in Giant Cell Arteritis. Effects of IL-6 receptor blockade with tocilizumab." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/668038.
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Giant cell arteritis (GCA) is a chronic granulomatous vasculitis affecting large- and medium-sized vessels. This disease can lead to different symptoms related to vascular or systemic inflammation, such as fever and visual loss, and its exact etiology remains to be elucidated. Current treatment of GCA patients is based on glucocorticoids administration. However, not all patients respond properly to this treatment and the disadvantages associated to glucocorticoids promotes the search for new therapeutic alternatives.
Blockade of IL-6 signaling with tocilizumab (TCZ), a humanized monoclonal antibody against IL-6 receptor (IL-6R), represents a newly promising alternative, supported by the results of two recently published clinical trials. However, beyond its implication in the acute phase response, the role of IL-6 in the pathogenesis of GCA and vascular inflammation is still unknown. GCA patients treated with TCZ also showed a decrease of acute-phase proteins, which are usually used to monitor disease activity. Therefore, the utilization of this monoclonal antibody remarks the urgency to find alternative biomarker not directly related with IL-6 signaling to monitor GCA patients treated with TCZ.
Considering all this information, the aim of this doctoral thesis was to better understand the role of IL-6 in GCA pathogenesis as well as the impact of IL-6R blockade with TCZ. In addition, we aimed to test the potential of osteopontin (OPN) as a biomarker of disease activity in patients treated with this monoclonal antibody.
The results from the present study show that IL-6 and IL-6R are remarkably increased in temporal artery lesions from GCA patients compared with control arteries. Co-culture experiments suggest that vascular smooth muscle cells (VSMC) may be an important source of IL-6. IL-6R was found upregulated in GCA lesions, particularly at the granulomatous areas. Co-culture experiments supported this result since IL-6R protein expression was increased in mononuclear cells when co-cultured with VSMC. Contrary to what was observed in tissue, serum levels of sIL-6R showed no differences between GCA patients and controls.
The artery culture model was used to better understand the impact of TCZ. IL-6R blockade resulted in a significant decrease in the mRNA expression of STAT3 and SOCS3 after 5 days in culture. However, phosphorylation levels of STAT3 were not modified by TCZ treatment. Co-culture results suggest that under inflammatory conditions the inhibitory effect of TCZ on STAT3 activation may be partially compensated by alternative mechanisms.
IL-6R blockade with TCZ also decreased CCL2 and increased the expression of CXCL9 and CXCL10 in cultured temporal arteries. Based on in vitro results, IL-6R blockade may promote an upregulation of CXCL9 and CXCL10 expression in mononuclear cells, that may explain the increased expression observed in cultured arteries. The upregulation of this chemokines may be due to an increase in STAT1 expression and activation after TCZ treatment. IL-6R blockade with TCZ also induced a reduction in the adhesion and migratory capacity of mononuclear cells. These results suggest that IL-6R blockade with TCZ may contribute to decrease tissue inflammation by limiting the advent of new
inflammatory cells. Further research is needed to better understand the molecules involved in TCZ modulation of these processes.
TCZ treatment of cultured arteries did not affect OPN expression in GCA lesions. Consistently, while levels of C-reactive protein (CRP) were virtually undetectable after IL- 6R blockade, serum concentration of OPN was similar in patients on glucocorticoid or TCZ maintained remission. All together, these data suggest that sOPN could be a useful biomarker of disease activity for TCZ treated patients. However, the role of sOPN needs to be further explored in larger studies with longitudinal cohorts.<br>L’arteritis de cèl·lules gegants (ACG) és una malaltia inflamatòria crònica d’etiologia desconeguda que afecta les arteries de mitjà i gran calibre. El tractament actual es basa en l’administració de glucocorticoides tot i que presenten efectes adversos i molts pacients experimenten recaigudes. Aquest fet promou la recerca de teràpies alternatives o complementaries. Recentment, s’han publicat els resultats de dos assajos clínics on s’ha vist que un nou fàrmac anomenat tocilizumab (TCZ), un anticòs que bloqueja el receptor de la IL-6 (IL-6R), podria ser una bona alternativa terapèutica per al pacients amb ACG. No obstant, el paper de la IL-6 en la patogènesi de l’ACG és encara desconegut. A més, l’ús del TCZ ha posat de manifest la necessitat de buscar biomarcadors alternatius als clàssicament utilitzats per monitoritzar els pacients, ja que el tractament amb aquest anticòs redueix l’expressió de les proteïnes de fase aguda, les quals són induïdes per la IL-6. Els objectius de la present tesi doctoral han estat per tant, entendre millor el paper de la IL-6 en l’ACG, així com estudiar l’impacte del bloqueig del IL-6R amb TCZ. Tanmateix, s’ha analitzat el potencial de l’osteopontiona (OPN) com a biomarcador alternatiu en pacients tractats amb aquest anticòs.
Els resultats del present estudi mostren que tant la IL-6 com el seu receptor es troben incrementats en les lesions de pacients amb ACG. El bloqueig del IL-6R amb TCZ té un efecte clar sobre l’expressió de les quimiocines CCL2, CXCL9 i CXCL10. A més, els resultats suggereixen que el tractament amb TCZ podria contribuir a disminuir la inflamació en els teixits al prevenir l’arribada de noves cèl·lules inflamatòries.
En relació al possible paper de l’OPN com a biomarcador en pacients tractats amb TCZ es va veure que els nivells de OPN en sèrum eren similar als dels pacients tractats amb glucocorticoides. Per contra, els nivells de proteïna C reactiva eren pràcticament indetectables en el grup de pacients tractats amb l’anticòs. En conjunt, els resultats mostren que l’OPN podria ser un bon biomarcador de l’activitat de la malaltia en pacients tractats amb TCZ.
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Knuth, Berenice Scaletzky. "Prevalência de depressão e níveis séricos de IL-6, em pacientes em hemodiálise." Universidade Catolica de Pelotas, 2012. http://tede.ucpel.edu.br:8080/jspui/handle/tede/283.
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Previous issue date: 2012-02-29<br>BACKGROUND: In hemodialysis patients, depression appears as the most common psychopathological condition. States of advanced chronic kidney disease and dialysis are associated with a state of chronic inflammation. Depression has been linked to activation of the immune system characterized by high levels of pro-inflammatory cytokines. In this study we investigated the possible correlations between depression, and interleukin-6 (IL-6) in hemodialysis patients.
METHODS: Seventy-five hemodialysis patients were enrolled in a cross-sectional study from September to November of 2011 in Pelotas/RS. Demographic data was obtained from a questionnaire and the Beck Depression Inventory (BDI), used to determine the presence or absence of depression symptoms. Biochemical parameters, dialysis dosage delivery, and IL-6 serum levels were measured.
RESULTS: Prevalence of depression among hemodialysis patients was 48% (BDI ≥ 14). In biochemical assessments, depressed patients showed a decrease in urea (p = 0.01) and increase of IL-6 (p = 0.04) levels. The correlation analysis between BDI scores and the biochemical variables showed that BDI was negative correlated with urea (p = 0.03) and potassium (p = 0.04), but not with IL-6 levels.
CONCLUSION: Hemodialysis patients with depression showed higher levels of IL-6 but the severity of depressive symptom was not correlated with levels of this cytokine.<br>A insuficiência renal crônica (IRC) é definida como a perda progressiva e irreversível da função renal. Em sua fase mais avançada, (chamada de fase terminal da insuficiência renal crônica) na qual os rins não conseguem mais manter a normalidade do meio interno, é necessário realizar a substituição da função renal. Tal procedimento pode ser realizado através de hemodiálise, diálise peritoneal ou transplante renal8. Atualmente, no Brasil, mais de 70.000 pacientes são dependentes de terapia renal substitutiva, com gasto anual de cerca de R$ 2,0 bilhões. Com base no grande número de grupos de risco, a previsão é que esse número possa duplicar nos próximos 5 anos, ultrapassando os 125 mil casos em 201016. As causas mais comuns de IRC são: diabetes (42,9%), hipertensão, doença de grandes vasos (26,4%), glomerulonefrite (9,9%) entre outras causas5.
Alexander Almeida e Alexandrina Meleiro, em 2000, descreveram que a depressão maior, apesar de provavelmente ser a desordem psiquiátrica mais comum nos pacientes com IRC, permanece largamente subdiagnosticada. Existem evidências de que a depressão diminui a aderência ao tratamento da IRC e influencie negativamente a qualidade de vida. Diante disto, revela-se um fator importante de risco para mortalidade cardiovascular, e aumente em até 15 vezes a taxa de suicídio, podendo ser um preditor independente de menor sobrevida1.
Estudos de revisão da literatura citam que a prevalência de depressão em pacientes em diálise varia de 0 a 100%, sugerindo que a prevalência dessa doença nesta população é ainda incerta10. A depressão maior, de acordo com os critérios do DSM-IV, pode se apresentar através de: humor deprimido, perda de prazer ou interesse notavelmente diminuído nas atividades prazerosas, distúrbios do sono, alteração do apetite e peso, perda de energia, ideação suicida entre outros6.
A depressão tem sido associada à ativação do sistema imunológico caracterizada por elevados níveis de citocinas proinflamatórias e proteínas positivas da fase aguda14. Alguns estudos demonstraram que os níveis de citocinas e TNF-α estão aumentados em pacientes com depressão14. As citocinas são um grupo de proteínas (polipeptídeos) responsáveis pelas mediações das conexões imunocerebrais e desempenham um papel importante na patogênese da depressão devido ao seu efeito nos neurotransmissores e neuro-hormonios15. Neste respeito à depressão maior, esta tem sido associada com o aumento continuado dos níveis de citocinas;
inclusive, tem sido significativamente implicada no desenvolvimento das desordens psiquiátricas, principalmente na depressão maior 13.
As citocinas e outras moléculas têm impacto nas funções neuropsiquiátricas como o humor e a cognição, através da modulação da anatomia e da função neuronal. A plasticidade neuronal é importante para a regulação do humor, cognição e comportamento durante toda a vida. As citocinas e outros fatores imunológicos desempenham um papel fundamental na modulação cerebral; entretanto, exposição crônica a citocinas proinflamatórias podem causar dano na plasticidade neuronal, contribuindo para desordens cognitivas e alteração de humor13.
Assim, uma vez que entre pacientes com IRC há grande incidência de sintomas depressivos, os objetivos deste estudo consistem em determinar a prevalência de depressão dos pacientes com IRC, em um serviço de hemodiálise, na cidade de Pelotas e identificar os possíveis biomarcadores, como a IL-6, nos fatores causadores do desenvolvimento da depressão. Tais fenômenos podem ajudar a melhorar o reconhecimento e o monitoramento dessa patologia
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Poe, Shaunta D. "Autocrine Effects of Catecholamines on Macrophage Release of Interleukin-6 (IL-6)." VCU Scholars Compass, 2006. http://hdl.handle.net/10156/1786.
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Chaulet, Charlotte. "Synthèse et étude du mécanisme d'action de nouveaux analogues de la thalidomide, dérivés du noyau 1H-pyrrolo (2, 3-b) pyridine, sur la modulation des cellules NK et la production des cytokines TNF-a et IL-6." Thesis, Tours, 2010. http://www.theses.fr/2010TOUR3802/document.
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La thalidomide est un sédatif hypnotique mis sur le marché pour la première fois en Allemagne en octobre 1957 et largement vendu par la suite dans 46 pays sous 51 noms commerciaux différents. Il fut également utilisé comme antiémétique chez les femmes enceintes et, dès le jour de Noël de l’année 1956, un premier enfant atteint de phocomélie naissait, six mois avant la mise sur le marché. La thalidomide fut retirée de la vente fin 1961, du fait de ses effets dévastateurs sur le développement fœtal. De nombreux mécanismes d’action de la thalidomide dans l’embryopathie ont été rapportés, notamment un effet antiangiogénique avec inhibition de la neurovascularisation au cours du développement des membres durant la vie fœtale. Par la suite, la thalidomide s’est imposée comme traitement dans un grand nombre de pathologies. Il a également été démontré qu’elle était capable d’induire une augmentation ou une inhibition de l’expression de chimiokines ou de facteur de croissance.L’élaboration de nouvelles molécules analogues plus efficaces reste au centre de nombreuses études de recherche. Sur la base des travaux effectués sur la régulation de la production de cytokines et de la modulation des lymphocytes NK par la thalidomide et ses analogues, nous avons travaillé autour du noyau 1H-pyrrolo[2,3-b]pyridine. Cette étude a permis de fonctionnaliser ce noyau sur diverses positions par différents types de synthèse organique : désulfonylation, réactions d’addtion 1,4 de type Michael, couplage peptidique, … et d’élaborer des molécules originales. Les composés synthétisés ont fait l’objet d’études pharmacologiques<br>Thalidomide is a sedative hypnotic on the market for the first time in Germany in October 1957 and subsequently sold widely in the 46 countries under 51 different trade names. It was also used as antiemetic in pregnant women and from the Christmas Day of 1956, a first child with phocomelia born, six months before placing on the market. Thalidomide was withdrawn from the market in late 1961, because of its devastating effects on fetal development. Many mechanisms of action of thalidomide embryopathy have been reported, including an antiangiogenic effect with inhibition of neurovascularisation during limb development during fetal life. Subsequently, thalidomide has emerged as a treatment of many diseases. It was also demonstrated its ability to induce an increase or inhibition of expression of chemokines or growth factor. The development of new molecules like more effective remains the focus of many research studies. Based on studies on the regulation of cytokines production and modulation of NK cells by thalidomide and its analogs, we worked on the 1H-pyrrolo [2,3-b] pyridine. This study led us to functionalize 7-azaindole on various positions and by different organic synthesis: desulfonylation, Michael addition, peptide coupling… These synthetized compounds have been tested in pharmacologic studies
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Woolley, Jane Alison. "The production, assessment and application of antibodies to human interleukin-6 (IL-6)." Thesis, Queen Mary, University of London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338809.
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Champa, Zachary J. "Modulation of IL-6 and IL-8 Expression in Ovarian Cancer Cells by a Small OrganicCompound." Ohio University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1460987166.
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Harré, Eva-Maria. "Die Rolle von Interleukin-6 (IL-6) in der zentralnervös vermittelten Fieberentstehung der Ratte." Wettenberg : VVB Laufersweiler, 2003. http://deposit.d-nb.de/cgi-bin/dokserv?idn=968960545.
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O'Brien, John D. "The Effect of Small Organic Compounds on Triple Negative Breast Cancer Cells." Ohio University / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1344436677.
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Correia, Josà Walter. "Polimorfismo -174g>C do gene de Interleucina-6 da Tuberculose Pulmonar." Universidade Federal do CearÃ, 2009. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=3567.
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nÃo hÃ<br>O objetivo do estudo foi investigar o perfil de produÃÃo de IL-6 em pacientes com tuberculose pulmonar ativa e avaliar o papel funcional do polimorfismo -174G>C do gene de IL-6 na produÃÃo sistÃmica desta citocina. Um total de 63 pacientes e 99 controles foi estudado, sendo 38 pacientes [25(65,8%) masculinos] e 63 controles [51 (81%) masculinos] para a dosagem de IL-6, enquanto, 42 pacientes [25 (60%) masculinos] e 79 controles [62(78,5%) masculinos] para o estudo do polimorfismo. Os pacientes foram selecionados dos centros de referÃncia da rede estadual de saÃde: Dona LibÃnia, Hospital de Messejana, Hospital de Maracanaà e Hospital Geral Dr. CÃsar Cals. O grupo controle foi selecionado no HEMOCE. Foi realizado teste de ELISA para a dosagem sÃrica de IL-6. O DNA genÃmico foi extraÃdo de sangue perifÃrico e o polimorfismo de IL-6 foi estudado por reaÃÃo de polimerase em cadeia utilizando iniciadores seqÃÃncia especÃficos. A dosagem sÃrica de IL-6 se mostrou elevada nos pacientes portadores de tuberculose em relaÃÃo aos controles (mediana = 4,3 pg/mL versus 0,5 pg/mL, p<0,001), porÃm nÃo exibiu diferenÃa entre os grupos de doentes sensÃveis e os resistentes ao tratamento especÃfico. Em relaÃÃo ao estudo funcional do polimorismo de IL-6, foi observado um robusto aumento dos nÃveis de IL-6 nos doentes portadores do genÃtipo GG (mediana=4,1 pg/mL, variaÃÃo 0,5-12,0 pg/mL), em relaÃÃo aos portadores dos genÃtipos GC e CC, sendo que nestes se observou uma expressÃo de IL-6 semelhante a dos controles (mediana=0,6 pg/mL, variaÃÃo 0,0-2,8 pg/mL), conferindo significÃncia estatÃstica com p=0,04. A relevÃncia deste estudo à mostrar in vivo o papel funcional do polimorfismo de IL-6 na tuberculose. Em conclusÃo, o genÃtipo GG de pacientes com tuberculose pulmonar ativa determina produÃÃo aumentada de IL-6.<br>The aim of this study was to investigate the profile of IL-6 production in patients with active pulmonary tuberculosis and to evaluate the functional role of polymorphism -174G>C in the systemic production of this cytokine. A total of 63 patients and 99 controls were studied. Among them 38 patients [25(65.8%) males] and 63 controls [51(81%) males] were studied for the IL-6 dosage. Moreover, 42 patients [25(60%) males] and 79 controls [62(78.5%) males] were studied for the -174G>C polymorphism. Patients were selected from Dona LibÃnia Center; Messejana Hospital, Maracanau Hospital and Dr. Cesar Cals General Hospital. The control group was selected from HEMOCE. An ELISA test was performed to measure IL-6 in peripheral blood. The genomic DNA was extracted from peripheral blood and IL-6 polymorphism was studied by polymerase chain reaction using sequence-specific primers. The IL-6 dosage showed an increase in patients with tuberculosis in relation to controls (An increase in IL6 dosage was found in patients with tuberculosis in relation to controls) (median= 4.3 pg/mL vs 0.5 pg/mL, p<0.001), but no difference was observed in drug-sensitive patients in comparison to drug-resistant ones. The genotype distribution showed no difference between patients and controls. In relation to the functional study, the IL-6 levels pointed out a significant increase in patients presenting GG genotype (median=4.1 pg/mL, range 0.5-12.0 pg/mL), in relation to GC and CC careers; these two latter genotypes presented similar IL-6 production as in healthy individuals with median=0.6 pg/mL, range 0.0-2.8 pg/mL, corroborating statistical significance with p=0.04. The relevance of this study is to show in vivo the functional role of IL-6 polymorphism in active pulmonary tuberculosis. Conclusion, the GG genotype in patients with pulmonary tuberculosis determines an increase in IL-6 systemic production.
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Loung, Le Anh. "Genetic variations in the interleukin-6(IL-6) gene : implication in coronary heart disease (CHD)." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406589.
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Yan, Jin, Ohannes Melemedjian, Theodore Price, and Gregory Dussor. "Sensitization of dural afferents underlies migraine-related behavior following meningeal application of interleukin-6 (IL-6)." BioMed Central, 2012. http://hdl.handle.net/10150/610216.
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BACKGROUND:Migraine headache is one of the most common neurological disorders, but the pathophysiology contributing to migraine is poorly understood. Intracranial interleukin-6 (IL-6) levels have been shown to be elevated during migraine attacks, suggesting that this cytokine may facilitate pain signaling from the meninges and contribute to the development of headache.METHODS:Cutaneous allodynia was measured in rats following stimulation of the dura with IL-6 alone or in combination with the MEK inhibitor, U0126. The number of action potentials and latency to the first action potential peak in response to a ramp current stimulus as well as current threshold were measured in retrogradely-labeled dural afferents using patch-clamp electrophysiology. These recordings were performed in the presence of IL-6 alone or in combination with U0126. Association between ERK1 and Nav1.7 following IL-6 treatment was also measured by co-immunoprecipitation.RESULTS:Here we report that in awake animals, direct application of IL-6 to the dura produced dose-dependent facial and hindpaw allodynia. The MEK inhibitor U0126 blocked IL-6-induced allodynia indicating that IL-6 produced this behavioral effect through the MAP kinase pathway. In trigeminal neurons retrogradely labeled from the dura, IL-6 application decreased the current threshold for action potential firing. In response to a ramp current stimulus, cells treated with IL-6 showed an increase in the numbers of action potentials and a decrease in latency to the first spike, an effect consistent with phosphorylation of the sodium channel Nav1.7. Pretreatment with U0126 reversed hyperexcitability following IL-6 treatment. Moreover, co-immunoprecipitation experiments demonstrated an increased association between ERK1 and Nav1.7 following IL-6 treatment.CONCLUSIONS:Our results indicate that IL-6 enhances the excitability of dural afferents likely via ERK-mediated modulation of Nav1.7 and these responses contribute to migraine-related pain behavior in vivo. These data provide a cellular mechanism by which IL-6 in the meninges causes sensitization of dural afferents therefore contributing to the pathogenesis of migraine headache.
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Gundamaraju, Anuradha. "The relationship between vitamin D intake and markers of inflammation (TNF-α and IL-6) in overweight and obese pregnant women in third trimester". University of Cincinnati / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1282167737.
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Sasser, Amy Kate. "The role of stromal fibroblasts and IL-6 in breast cancer progression." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1172866243.
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Hauk, Thomas. "Einfluss von Makrophagen und IL-6 auf die axonale Regeneration bei der adulten Ratte." [S.l. : s.n.], 2008. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-65621.
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Holmes, Anna Greer, and not supplied. "Role of interleukin-6 in states of metabolic health and disease." RMIT University. Medical Sciences, 2006. http://adt.lib.rmit.edu.au/adt/public/adt-VIT20070131.121620.
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Obesity and type 2 diabetes are the most prevalent metabolic diseases affecting over 50% of people in the western world. Although the pathogenesis of type 2 diabetes is not fully understood, growing evidence links this disease to a state of chronic inflammation, which occurs in metabolically active tissue such as the liver, adipose tissue and skeletal muscle and results in the secretion of inflammatory cytokines, of which interleukin-6 (IL-6) is one. It is generally accepted that elevations in the plasma and/or tissue of this family of cytokines have a negative effect on whole body glucose homeostasis. While there is compelling evidence for the negative effects of resistin and TNF-á on insulin sensitivity, the role of IL-6 in the etiology of insulin resistance is not fully understood. The notion of negative effects of IL-6 in metabolic processes is further confounded by the marked elevations of IL-6 which occur in conjunction with the beneficial activity of exercise. We firstly sought to examine the effect of the lipolytic hormone adrenaline on IL-6 expression and release in order to establish whether IL-6 acts independently of adrenaline in the regulation of fat metabolism. Reporting the absence of an effect of adrenaline on IL-6, we then investigated the role of IL-6 on metabolic processes in humans at rest and during exercise in circumstances where lipolysis was inhibited. Marked increases in IL-6 circulating protein and tissue gene expression were observed with exercise and further so with fatty acid suppression. In a mouse model of IL-6 depletion marked insulin sensitivity was observed, which was reversed with IL-6 treatment. In a mouse model with normal endogenous IL-6 levels IL-6 treatment also impaired glucose tolerance. Contrastingly, in a rat model both chronic and acute IL-6 treatment improved glucose tolerance In summary, studies from this thesis suggest that, rather than being causally related to insulin resistance, the cytokine IL-6 increases lipolysis, fat oxidation, and glucose metabolism in insulin sensitive tissues in humans. This does not appear to be the case in the mouse, where contrasting actions are observed, perhaps due to differences in the reliance of various parameters for metabolic processes between the species.
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Harré, Eva-Maria [Verfasser]. "Die Rolle von Interleukin-6 (IL-6) in der zentralnervös vermittelten Fieberentstehung der Ratte / Eva-Maria Harré." Wettenberg : VVB Laufersweiler, 2003. http://d-nb.info/968960545/34.
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Habowski, Scott. "Effects of the IL-6 Gene Polymorphism -174G/C on Interleukin-6 Production and Endurance Exercise Performance." Kent State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=kent1532023529854917.
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Christian, Lisa M. "Stress, Depression, And Inflammatory Immune Responses During Pregnancy." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1211218519.
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Ha, Byeong Keun. "Corticotropin releasing factor (CRF) and interleukin-6 (IL-6) type cytokines as possible trophic factors in cerebellar development /." The Ohio State University, 1999. http://rave.ohiolink.edu/etdc/view?acc_num=osu1488188894438717.
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Silva, Ítala Cristine. "Papel da interleucina 6 (IL-6) na resposta inflamatória neutrofílica durante a infecção por Leishmania infantum>." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/17/17147/tde-06062017-170957/.
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As leishmanioses são um conjunto de doenças causadas pela infecção com protozoários do gênero Leishmania. No Brasil, o parasita L. infantum provoca a manifestação de uma doença sistêmica e crônica, conhecida como leishmaniose visceral (VL), que, quando não tratada, pode levar o indivíduo à óbito. A gravidade da leishmaniose visceral vem sendo associada ao aumento do nível sistêmico de IL- 6 em pacientes sintomáticos. Ainda não está claro como o aumento dessa citocina coordena a progressão da doença. Nós demonstramos durante a infecção por L. infantum experimental há produção dessa citocina nos órgãos alvos. Em decorrência dessa via, animais deficientes para IL-6 (IL-6-/-) são suscetíveis a infecção por apresentar maior número de parasitos nos órgãos alvo e por desenvolverem uma fraca resposta inflamatória em função da diminuição do infiltrado inflamatório. Como consequência, há o aumento de CXCL2 que medeia o recrutamento de neutrófilos no baço. Apesar de aumentada em animais IL-6-/- os neutrófilos apresentam um estado menos ativado. A produção dos principais mediadores de morte dos parasitos, como espécies reativas de oxigênio (ROS) e o óxido nítrico (NO), estão comprometidas e favorecem a disseminação do parasito em animais IL-6-/-. Por outro lado, a Il-6 não interfere na produção de citocinas pró-inflamatórias e na proliferação de linfócitos Th1, atuando somente em linfócitos Th17 no início da infecção, sugerindo que o controle da resposta inflamatória é dependente de mecanismos inatos. Em humanos, identificamos dois genes modulados pela via de sinalização da IL-6. Os genes Hsbp1 e AR estão up-regulados em pacientes com a doença ativa e são genes associados com a migração e a produção de neutrófilos na medula óssea, possivelmente envolvidos com a neutropenia em pacientes com LV. Juntos, os dados mostram que a via de sinalização da IL-6 tem papel importante na modulação da resposta imune de neutrófilos, e em promover proteção durante a LV.<br>Leishmaniasis is a group of diseases caused by infection with protozoa of the genus Leishmania. In Brazil, the parasite L. infantum causes the manifestation of a systemic and chronic disease, known as visceral leishmaniasis (VL), which, when left untreated, can lead to death. The severity of visceral leishmaniasis has been associated with an increase in the systemic level of IL-6 in symptomatic patients. It is not yet clear how the increase in this cytokine coordinates the progression of the disease. We demonstrated during the infection by experimental L. infantum there is production of this cytokine in the target organs. As a result of this pathway, IL-6 ( IL- 6-/-) deficient animals are susceptible to infection because they present a higher number of parasites in the target organs and they develop a poor inflammatory response due to the decrease of the inflammatory infiltrate. As a consequence, there is an increase in CXCL2 that mediates the recruitment of neutrophils in the spleen. Although increased in IL-6-/- animals the neutrophils have a less activated state. The production of the main mediators of parasite death, such as reactive oxygen species (ROS) and nitric oxide (NO), are compromised and favor the spread of the parasite in IL-6-/- animals. On the other hand, IL-6 does not interfere in the production of proInflammatory cytokines and Th1 lymphocyte proliferation, acting only on Th17 lymphocytes at the beginning of the infection, suggesting that the control of the inflammatory response is dependent on innate mechanisms. In humans, we identified two genes modulated by the IL-6 signaling pathway. The Hsbp1 and AR genes are up-regulated in patients with the active disease and are genes associated with the migration and production of neutrophils in the bone marrow, possibly involved with neutropenia in patients with VL. Together, the data show that the IL-6 signaling pathway plays an important role in modulating the neutrophil immune response, and in promoting protection during LV.
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Poncet, Nadège. "La voie ERK1/2 : point d'intégration et de convergence des connexions entre voies de signalisation dans les cellules épithéliales de prostate normale." Phd thesis, Université Claude Bernard - Lyon I, 2010. http://tel.archives-ouvertes.fr/tel-00824334.
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Le développement et l'homéostasie cellulaire de la prostate impliquent le contrôle strict des voies de signalisation induites par les androgènes et les facteurs de croissance. Ces diverses voies sont profondément altérées dans le cancer de la prostate, notamment lors des stades les plus avancés. Dans ce travail, une lignée immortalisée à partir de l'épithélium de prostate humaine, la lignée RWPE-1, a été utilisée pour étudier certains signaux régulant la prolifération cellulaire, ainsi que les connexions entre les voies de signalisation correspondantes. La prolifération des cellules RWPE-1 est sous la dépendance de l'EGF (Epidermal Growth Factor) qui intervient physiologiquement dans le développement épithélial. Les récepteurs apparentés à l'EGF-R sont également impliqués dans la prolifération au cours de la progression tumorale. La prolifération des cellules RWPE-1 en réponse à l'EGF est strictement dépendante de la voie ERK1/2, qui est donc considérée comme un point d'intégration des signaux. L'utilisation d'inhibiteurs du récepteur aux androgènes a permis de montrer le rôle essentiel qu'il joue dans l'activation d'ERK1/2 en réponse à l'EGF. Le récepteur aux androgènes s'associe avec plusieurs molécules de signalisation dans les cellules RWPE-1. Je démontre ici pour la première fois une association entre le récepteur aux androgènes et la kinase Raf-1, activatrice de la voie ERK1/2. Ainsi, le récepteur aux androgènes contrôlerait directement un processus essentiel à la prolifération épithéliale selon un mode d'action non-génomique. Par ailleurs, j'ai montré que la réponse proliférative des cellules RWPE-1 à l'IL-6 requiert l'activation de la voie ERK1/2, et l'activité kinase de l'EGF-R, suggérant la transactivation de ce récepteur par l'IL-6. L'utilisation de divers inhibiteurs chimiques a permis de démontrer que les métalloprotéases de la famille ADAM (a disintegrin and metalloprotease), notamment ADAM17, sont impliquées dans ce processus. Ainsi, l'activation de protéines ADAM par l'IL-6 conduirait au clivage d'un ligand membranaire de l'EGF-R, aboutissant à l'activation de la voie ERK1/2. Ce nouveau mécanisme pourrait être impliqué dans les situations inflammatoires conduisant à une prolifération excessive de l'épithélium prostatique, prélude à la transformation tumorale. En conclusion, les voies de signalisation étudiées sont fortement connectées dans les cellules épithéliales normales. Les deux nouveaux mécanismes décrits ici aboutissent à l'activation des kinases ERK1/2, point d'intégration et de convergence des voies de signalisation dans les cellules épithéliales de prostate normale.
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Souza, Letícia da Silva. "Velocidade de crescimento e níveis de interleucina-6 na artrite idiopática juvenil." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2008. http://hdl.handle.net/10183/14052.
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Objetivos: Avaliar associações da velocidade de crescimento com marcadores inflamatórios e dose cumulativa de glicorticóide em uma coorte de pacientes com Artrite Idiopática Juvenil acompanhados por 1 ano. Material e Métodos: Foram avaliados 79 pacientes com AIJ segundo critérios da ILAR. A atividade clínica da doença foi classificada por médicos reumatologistas pediátricos. Os dados antropométricos foram mensurados e classificados de acordo com as normas da Organização Mundial da Saúde. Foram utilizadas curvas de velocidade de crescimento segundo Tanner; considerou-se baixa velocidade de crescimento valores de escore Z ≤ -2. Concentrações séricas de IL-6 foram mensuradas por ELISA no período basal, e valores acima de 1 pg/ml foram considerados elevados. Resultados: Baixa velocidade de crescimento teve uma prevalência de 25,3% e esteve associada com atividade da doença no período do seguimento (p=0,085), valores elevados de IL-6 (interleucina-6) (p=0,003), velocidade de sedimentação globular (VSG) (p=0,022) e proteína C reativa (PCR) (p=0,001) e maior dosagem cumulativa de glicocorticóide (0=0,044). Na regressão linear múltipla tendo como variável dependente a velocidade de crescimento, observou-se que somente os níveis elevados de IL-6 foram independente e negativamente associados com a velocidade de crescimento (p=0,025). Conclusão: Baixa velocidade de crescimento é altamente prevalente em crianças com AIJ. Níveis elevados de IL-6 têm um importante impacto negativo no crescimento desses pacientes, enquanto a exposição ao glicocorticóide total parece ser um fator secundário.<br>Objective: To evaluate associations of growth velocity with inflammatory markers and cumulative dose of glucocorticoid in a cohort of patients with Juvenile Idiopathic Arthritis (JIA) followed during 1 year. Methods: Seventy-nine patients were evaluated by criteria according to the ILAR. The disease activity was evaluated by a pediatric rheumatologist. The anthropometic data were measured and classified according to the World Health Organization standards. Growth velocity curves were used according to Tanner, values below the Z-score ≤ -2 were considered low growth velocity. Serum concentrations of IL-6 were measured by ELISA in the baseline period, and values over 1pg/ml were considered as elevated. Results: The prevalence of low growth velocity was 25.3%, and it was associated with: active disease on follow-up visit (p=0,085), elevated interleukin-6 (IL-6) (p=0,003), erythrocyte sedimentation rate (ESR) (p=0,022) and C-reactive protein (CRP) (p=0,001) and higher cumulative glucocorticoid doses (0=0,044). In the multiple linear regression with growth velocity as the dependent variable, only elevated IL-6 levels were independently and negatively associated with growth velocity (p=0,025). Conclusion: Low growth velocity is highly prevalent in children with JIA. Elevated IL-6 levels seem to have an important negative impact on growth in these children, while total glucocorticoid exposure appears to be a secondary factor.
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Hosseinzadeh, Attar Mohammad Javad. "Adipose tissue release of interleukin-6 (IL-6) and asymmetric dimethyl arginine (ADMA) : implications for obesity associated metabolic disease." Thesis, University College London (University of London), 2004. http://discovery.ucl.ac.uk/1446597/.
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Obesity is associated with the development of various metabolic diseases. Adipose tissue-derived factors may underlie this relationship. Two novel adipose signals associated with increased risk of coronary heart disease were investigated; interleukin-6 (IL-6) and the endogenous nitric oxide inhibitor, asymmetric dimethyl arginine (ADMA). The effect of the cyclo-oxygenase (COX) pathway on basal adipose IL-6 production was examined. Basal COX-2 expression was detected in adipose tissue explants. There was a dose-dependent decrease in adipose IL-6 release by a non-selective COX inhibitor, aspirin. Cyclic AMP, and not Ca2+, was the intracellular mediator of IL-6 release. PGE2 EP2 and 4 signalling is mediated by elevation in intracellular cAMP and agonists for these receptors elevated IL-6. Thus, basal IL-6 secretion occurs through increased COX-2 mediated PGE2 release signalling via EP4 receptors and elevated intracellular cAMP. The role of the COX pathway was also investigated in adipogenesis. Aspirin and SC-560, a selective COX-1 inhibitor, inhibited adipocyte differentiation mainly by down-regulating adipogenic transcription factors. However, NS-398, a COX-2 selective inhibitor, was found to have no such effect. Thus, adipogenesis was found to be regulated by a COX-1 mediated mechanism. ADMA, an endogenous NO inhibitor, is cleared mainly by catabolism by DDAH. Significant amounts of DDAH 1 and 2 mRNA and protein were expressed in mouse and human adipose tissue and adipocytes. In human subjects, the abdominal sub-cutaneous adipose tissue released ADMA in vivo and circulating levels in morbid obesity were elevated. Furthermore, weight loss increased adipose DDAH expression and decreased systemic ADMA levels. In vitro studies also showed a direct correlation between the amount of adipose tissue and its release of ADMA. Thus, genetic, dietary and pharmacological disruption of DDAH altered adipose ADMA release. In conclusion, this work showed that two important enzymes, COX and DDAH, in adipose tissue have the capacity to modulate cardiovascular risk in obesity by their regulation of IL-6 synthesis, adipogenesis and the release of ADMA.
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Chan, Ming Hang (Stanley), and stanley chan@baker edu au. "Investigation of The Intracellular Signalling Pathway for Interleukin-6 Gene Expression in Skeletal Muscle." RMIT University. Medical Sciences, 2007. http://adt.lib.rmit.edu.au/adt/public/adt-VIT20080206.091026.
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Palmer, Jodie. "The IL-6 type cytokine family in prostate cancer." Monash University, Centre for Functional Genomics and Human Disease, 2003. http://arrow.monash.edu.au/hdl/1959.1/9441.
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Palmqvist, Py. "Osteotropic cytokines : expression in human gingival fibroblasts and effects on bone." Doctoral thesis, Umeå : Umeå universitet, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-960.
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Miranda, Julise Cunha. "Avaliação da expressão de hepcidina e produção de IL-6 por monócitos de indivíduos idosos." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/60/60135/tde-25082009-152450/.
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Anemia em idosos está relacionada ao aumento da morbidade e mortalidade desta população. As causas das anemias em idosos podem ser divididas em três grupos: anemia das doenças crônicas (ADC), anemia por deficiência de nutrientes, na qual se inclui a anemia por deficiência de ferro (ADF) e anemias de causas não-identificadas. A hepcidina constitui uma importante ligação entre defesa primária, inflamação e metabolismo do ferro. A hepcidina é induzida, principalmente, pela interleucina-6 (IL-6), atua como regulador negativo da absorção de ferro e é mediadora da retenção de ferro por monócitos e macrófagos durante inflamação ou infecção. Estudos recentes têm demonstrado o papel da produção desse hormônio por monócitos na homeostase do ferro, num modelo autócrino e parácrino. O presente trabalho teve por objetivo geral correlacionar os níveis de IL-6 produzidos por monócitos em cultura e a expressão de hepcidina em monócitos de indivíduos com ADC, com inflamação sem anemia, ADF e com anemias não-identificadas e, por objetivos específicos, verificar a eficiência de parâmetros hematológicos clássicos em avaliar o status férrico de idosos; comparar os níveis de IL-6 produzidos por células monocíticas em cultura, nos diferentes grupos de estudo, e relacioná-los com os parâmetros utilizados para caracterização das anemias; comparar os níveis de expressão de hepcidina em células monocíticas, nos diferentes grupos de estudo, e relacioná-los com o estado inflamatório e com os parâmetros utilizados para caracterização das anemias. Para isso, os pacientes foram avaliados através de parâmetro bioquímicos (glicemia, creatinina sérica, -glutamil transferase, proteínas totais e albumina, por método colorimétrico e proteína C-reativa, por imunoturbidimetria ultra-sensível) e hematológicos (hemograma completo, utilizando o contador de células Micros 45 ABX®, França, e extensão sangüínea corada por Leishman, ferritina sérica, por método imunoquimioluminescente, receptor de transferrina solúvel, por ensaio imunoenzimático e cálculo do índice sTfR/log ferritina). A determinação dos níveis de IL-6 foi feita por imunoensaio enzimático quantitativo em sobrenadante de cultura de monócitos e a dos níveis de expressão do RNAm da hepcidina em monócitos pela Reação em Cadeia da Polimerase em Tempo Real (RT-PCR). Os níveis séricos de ferritina estavam estatisticamente diminuídos na população com ADF, embora sem atingir os valores preconizados para diagnóstico de deficiência de ferro. Os níveis de receptor de transferrina solúvel (sTfR) e o índice sTfR/log ferritina estavam elevados em pacientes com ADF, porém, o índice não aumentou a sensibilidade da medida do receptor para pacientes idosos. Estes resultados obtidos sugerem que valores de normalidade para níveis de ferritina e índice receptor-ferritina devem ser revistos para a população idosa. Houve aumento da concentração de IL-6 em sobrenadante de cultura de monócitos no grupo Inflamação quando comparado com o grupo Anemia. Os níveis de IL-6 correlacionaram-se positivamente com os níveis da proteína C-reativa e número de leucócitos da população em estudo, porém, não houve correlação com os níveis de RNAm de hepcidina expressos por monócitos. A expressão de RNAm de hepcidina em monócitos mostrou correlação positiva com os níveis séricos de ferritina, porém, não foi diferente entre os grupos de estudo.<br>Anemia in elderly is associated with increased morbidity and mortality in this population. The causes of anemia in elderly can be divided into three groups: anemia of chronic diseases (ACD), anemia of nutrients deficiency, which include iron deficiency anemia (IDA) and unexplained anemias. Hepcidin is an important link between primary defense, inflammation and iron metabolism. The hepcidin is mainly induced by the Interleukin-6 (IL-6), it acts as a negative regulator of iron absorption and it is mediating of iron retention by monocytes and macrophages during inflammation or infection. Recent studies have been demonstrating the role of this hormone production by monocytes in the iron homeostasis, in autocrine and paracrine fashion. The general objective of this study was to correlate the levels of monocyte-derived IL-6 in culture and the monocyte hepcidin mRNA expression in patients with ACD, with inflammation without anemia, IDA and with unexplained anemias. The specific objectives are to verify the efficiency of classic haematological parameters in evaluating the iron status in elderly; to compare the levels of monocyte-derived IL-6 in culture, in different study groups, and to relate them with the parameters used for anemias characterization; to compare the levels of monocyte hepcidin mRNA expression, in different study groups, and to relate them with the inflammatory state and with the parameters used for anemias characterization. For that, the patients were evaluated by biochemical parameter (blood glucose, serum creatinine, -glutamyl transferase, total proteins and albumin, by colorimetric method and high-sensitivity C-reactive protein, measured by immunoturbidimetric assay) and hematological (complete blood count, using the cells accountant Micros 45 ABX®, and peripheral blood film for Leishmans staining morphology, serum ferritin level by immuno-quimioluminescent assay, soluble transferrin receptor, by Enzyme Linked Immuno Sorbent Assay (ELISA) and sTfR/log ferritin index). The determination of IL-6 levels was performed by quantitative ELISA in monocyte culture supernatants and monocyte hepcidin mRNA levels by Real-Time Polymerase Chain Reaction (RT-PCR). Although serum ferritin levels were statistically decreased in IDA population, it did not reach the values recommended for diagnosis of iron deficiency. The soluble transferrin receptor (sTfR) levels and the sTfR/log ferritin index were significantly higher in IDA group, however, the index did not increase the sensibility of the sTfR measure for elderly. These results suggest that normality values for ferritin levels and sTfR/log ferritin index should be reviewed for elderly population. There was increase of levels of monocyte-derived IL-6 in culture in Inflammation group compared with Anemia group. The IL-6 levels were positively correlated with C-reactive protein levels and leukocyte number of the patients, however, there was not correlation with monocyte hepcidin mRNA levels. The monocyte hepcidin mRNA levels showed positive correlation serum ferritin levels, however, it was not different between the study groups.
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Schlichting, Nadine. "Palmitat induzierte Expression von IL-6 und MCP-1 in humanen Detrusormyozyten vs. bakteriell induzierter Entzündungsreaktion - ein möglicher Zusammenhang zwischen diabetischen Stoffwechsel und Infektionen der Harnblase." Doctoral thesis, Universitätsbibliothek Leipzig, 2011. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-67731.
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Adipöse Patienten und Typ-2-Diabetiker zeigen ein erhöhtes Risiko für Harnwegsinfekte. Die Ursache der höheren Prävalenz ist noch nicht nachhaltig geklärt. Bekannt ist, dass Typ-2-Diabetiker erhöhte Konzentrationen freier Fettsäuren im Blut aufweisen. Der veränderte Fettstoffwechsel könnte neben bakteriellen Ursachen ein möglicher Grund für abakterielle Entzündungsreaktionen der Harnblase sein. Zur Prüfung dieser Hypothese wurden zeit- und konzentrationsabhängig kultivierte humane Detrusormyozyten im Vergleich zur Lipopolysaccharid (LPS) induzierten Entzündungsreaktion mit Palmitat stimuliert. Es wurde geprüft, ob eine autokrine und/oder endokrine Regulation des IL-6-Signalwegs vorliegt. Im Fokus standen insbesondere die IL-6- und MCP-1-Expression und deren möglichen regulatorischen Proteine gp80, gp130, NF-κB, STAT3, SOCS3 und MEK1. Die Stimulationsversuche mit LPS und Palmitat zeigen einen differenten zeit- und konzentrationsabhängigen Effekt auf die IL-6- und MCP-1-Expression in den humanen Detrusormyozyten. LPS und Palmitat induzieren eine zeitabhängige autokrine Regulation der IL-6-Signalkaskade über phosphoryliertes STAT3 und Feedback-mechanismen via SOCS3. Sowohl LPS als auch Palmitat bewirken über 48h eine mögliche endokrine Regulation des IL-6-Signalwegs. Zusammenfassend zeigt die Palmitatstimulation zeit- und konzentrationsabhängig einen stärkeren Effekt auf die IL-6-Signalwirkung als die Stimulation mit LPS<br>Background: Urinary tract infections (UTI) are more frequent in type-2 diabetes mellitus patients than in subjects with normal glucose metabolism. The mechanisms underlying this higher prevalence of UTI are unknown. However, cytokine levels are altered in diabetic patients and may thus contribute to the development of UTI. Increased levels of free fatty acids (FFA), as observed in obese patients, can induce IL-6 production in various cell types. Therefore we studied the effects of the free fatty acid palmitate and bacterial lipopolysaccharide (LPS) on interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1) expression and secretion in cultured human bladder smooth muscle cells (hBSMC). Methodology/Principal Findings: Biopsies were taken from patients undergoing cystectomy due to bladder cancer. Palmitate or LPS stimulated hBSMC were analysed for the production and secretion of the IL-6, gp80, gp80soluble, gp130, MCP-1, pSTAT3, SOCS3, NF-kB and SHP2 by quantitative PCR, ELISA, Western blotting, and confocal immunofluorescence. In signal transduction inhibition experiments we evaluated the involvement of NF-kB and MEK1 in IL-6 and MCP-1 regulation. Palmitate upregulates IL-6 mRNA expression and secretion via NF-kB dependent pathways in a concentration- and timedependent manner. MCP-1 was moderately upregulated by palmitate but was strongly upregulated by LPS involving NF-kB and MEK1 dependent pathways. Soluble IL-6 receptor (gp80soluble) was downregulated by palmitate and LPS, while membrane-bound gp80 was moderately upregulated. LPS increased SOCS3 and SHP2, whereas palmitate only induced SOCS3. Secondary finding: most of the IL-6 is secreted. Conclusions/Significance: Bacterial infection (LPS) or metabolic alterations (palmitate) have distinct effects on IL-6 expression in hBSMC, (i) short term LPS induced autocrine JAK/STAT signaling and (ii) long-term endocrine regulation of IL-6 by palmitate. Induction of IL-6 in human bladder smooth muscle cells by fatty acids may represent a pathogenetic factor underlying the higher frequency and persistence of urinary tract infections in patients with metabolic diseases
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Hirotsu, Akiko. "Maternal exposure to volatile anesthetics induces IL-6 in fetal brains and affects neuronal development." Kyoto University, 2020. http://hdl.handle.net/2433/253146.
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Messetti, Ana Camila Pereira 1980. "Análise da correlação entre condição periodontal e polimorfismos nos genes das citocinas IL-1, IL-6, TNF-alpha e da enzima paraoxonase em indivíduos afetados ou não com Diabetes Melito tipos I e II." [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/288574.
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Orientador: Rebeca de Souza Azevedo<br>Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba<br>Made available in DSpace on 2018-08-23T13:31:17Z (GMT). No. of bitstreams: 1
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Previous issue date: 2013<br>Resumo: A doença periodontal (DP) é uma doença inflamatória crônica de ampla distribuição etária e mundial, que resulta da interação entre fatores etiológicos heterogêneos e que pode sofrer influência ambiental e sistêmica, especialmente na presença do diabetes melito (DM). Os mecanismos que envolvem a associação entre o DM e a presença da DP ainda não estão completamente elucidados, mas as características genéticas ou epigenéticas do hospedeiro, como os polimorfismos genéticos, podem influenciar esta relação. Dessa forma, o objetivo deste estudo foi avaliar o envolvimento de polimorfismos nos genes de IL1-? (-889), de IL1-? (+3984), de IL-6 (-174), de TNF-? (-308) e da paraoxanase (-192) e da paraoxonase (-55) no desenvolvimento de DP e DM em um grupo de pacientes brasileiros. Os polimorfismos rs1800587 e rs1143634 no gene IL-1, rs1800796 no gene IL6, rs1800629 no gene TNF-?, e rs662 e rs854560 no gene paraoxanase foram genotipados em 302 adultos, dos quais 96 eram diabéticos com DP (ADM+DP), 20 eram diabéticos com saúde periodontal (ADM-DP), 112 eram normoglicêmicos com DP (AN+DP) e 74 eram normoglicêmicos com saúde periodontal (AN-DP); e em 88 crianças e adolescentes, dos quais 11 eram diabéticos com gengivite (CDM+G), 15 eram diabéticos com saúde gengival (CDM-G), 30 eram normoglicêmicos com gengivite (CN+G) e 32 eram normoglicêmicos com saúde gengival (CN-G). No grupo de pacientes adultos, a presença do alelo T no polimorfismo rs1143634 no gene IL1-? foi mais frequente nos indivíduos ADM+DP que nos indivíduos AN-DP, gerando um OR de 14,9 (95% IC: 8,6-25,9; p<0,0001); a presença do alelo A no polimorfismo rs1800629 no gene TNF-? foi mais frequente nos indivíduos ADM+DP que nos indivíduos AN-DP, gerando um OR de 22,7 (95% IC: 6,96 -74,5 p<0,0001), e a presença do alelo C no polimorfismo rs1800796 no gene IL6 foi mais frequente nos indivíduos ADM+DP que nos indivíduos AN+DP, gerando um risco de recorrência de 2,38 (95% IC:1,61-3,5; p<0,0001), e que nos indivíduos AN-DP, gerando risco de recorrência de 2,87 (1,79-4,5; p<0,0001). No grupo de pacientes crianças e adolescentes, a presença do alelo C no polimorfismo rs1800796 no gene IL-6 foi mais frequente em indivíduos CN+G que nos indivíduos CN-G, gerando um risco de recorrência de 121,1 (95% IC:32,3-145,3; p<0,0001), e foi mais frequente nos indivíduos CDM+G que nos indivíduos CN-G, gerando um risco de recorrência de 104 (95% IC:11,4-136,6; p<0,0001). Os resultados deste estudo evidenciam a associação dos polimorfismos rs1143634 no gene IL1-?, rs1800796 no gene IL6 e rs1800629 no gene TNF-? com a suscetibilidade genética ao desenvolvimento de DP e/ou DM na população adulta estudada; e a associação do polimorfismo rs1800796 no gene IL-6 com a suscetibilidade genética ao desenvolvimento de DP e/ou DM na população de crianças e adolescentes estudada<br>Abstract: Periodontal disease (PD) is a chronic inflammatory disease of worldwide distribution that may affect all age groups, and results from the interaction between heterogeneous etiologic factors, such as environmental and systemic influence, especially in the presence of diabetes mellitus (DM). Mechanisms involving the association between DM and the presence of PD are still not fully elucidated, but the genetic or epigenetic alterations of the host, such as the genetic polymorphisms may influence this relationship. Thus, the aim of this study was to evaluate the involvement of polymorphisms in the genes of IL1-? (-889), IL1- (+3984), IL-6 (-174), TNF-? (-308) and paraoxanase (-192) and paraoxonase (-55) in PD and/or DM development in a group of Brazilian patients. The polymorphisms rs1800587 and rs1143634 from IL1 gene, rs1800796 form IL6 gene, rs1800629 from TNF-? gene, and rs662 and rs854560 from paraoxanase gene were genotyped in 302 adults, of whom 96 were diabetic with PD (ADM+PD), 20 were diabetics with periodontal health (ADM-PD), 112 were normoglycemic with PD (AN+PD) and 74 were normoglycemic with periodontal health (AN-PD); and in 88 children and adolescents, of whom 11 were diabetic patients with gingivitis (CDM+G), 15 were diabetics with gingival health (CDM-G), 30 were normoglycemic with gingivitis (CN+G) and 32 were normoglycemic with gingival health (CN-G). In the group of adult patients, the presence of T allele at the rs1143634 polymorphism in the IL1-? gene was more frequent in ADM+PD than in AN-PD, generating an OR of 14, 9 (95% CI :14,9-25, 9; p <0.0001), the presence of A allele at the rs1800629 polymorphism in the TNF-? gene was more frequent in ADM+PD than in AN+PD, generating an OR of 22,7 (95% CI 6.96 -74.5; p <0.0001), and the presence of C allele at the rs1800796 polymorphism in the gene IL6 was more frequent in ADM+PD than in AN+PD, generating an OR of 2.38 (95% CI :1,61-3, 5; p <0.0001), and it was more frequent in ADM+PD than in AN-PD, generating an OR of 2.87 (1.79 to 4.5, p <0.0001). In the group of children and adolescents, the presence of C allele at the rs1800796 polymorphism in the IL6 gene is more frequent in NC+G than in NC-G, generating an OR of 121.1 (95% CI :32,3-145, 3; p <0.0001), and it was more frequent in CMD+G than in NC-G, generating an OR of 104 (95% CI :11,4-136,6; p <0.0001). The results of this study show the association of rs1143634 polymorphisms in the IL1-? gene, rs1800796 in the IL6 gene, and rs1800629 in the TNF-? gene with genetic susceptibility to PD and/or DM development in the adult population studied, and association of the polymorphism rs1800796 in the IL6 gene with genetic susceptibility for PD and/or DM development in the children and adolescents population studied<br>Mestrado<br>Estomatologia<br>Mestra em Estomatopatologia
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Menegat, Juliana Santos Bittencourt. "Níveis elevados de IL-6 no fluido gengival de pacientes com periodontite crônica e retrocolite ulcerativa idiopática." Universidade do Estado do Rio de Janeiro, 2009. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=3481.
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O nosso objetivo foi mensurar os níveis de Interleucina-6 (IL-6) no fluido gengival de pacientes com periodontite e doença inflamatória intestinal (DII), comparando-os com pacientes sistemicamente saudáveis, com periodontite. Como objetivo secundário será avaliada a IL-6 no soro desses pacientes. Foram selecionados 15 pacientes com doença de Crohn (DC, idade média 38.2, DP 11.4 anos), 15 com retrocolite ulcerativa idiopática (RCUI, 45.0 10.5 anos) e 15 pacientes saudáveis (C, 42.1 7.8 anos). A Profundidade de bolsa (PB), nível de inserção clínica (NI), presença de placa e de sangramento a sondagem foram avaliados em seis sítios por dente. O fluido gengival foi coletado de quatro sítios com periodontite (PP: PB ≥ 5mm, NI ≥ 3mm) e quatro sítios com gengivite (GP: PB ≤ 3mm e NI≤ 1mm), em dentes diferentes, com pontas de papel absorvente pré-fabricadas. O soro destes pacientes também foi coletado. A análise da IL-6 foi realizada pelo LUMINEX. A quantidade total e concentração da IL-6 estavam significantemente maiores no fluido gengival dos sítios PP do grupo RCUI quando comparados aos sítios PP do grupo controle (p=0.028; p=0.044, respectivamente). O grupo DC apresentou a quantidade total de IL-6 significantemente maior no sítio PP do que no GP (p=0.028). Já no soro, a IL-6 não diferiu entre os grupos. Sendo assim, pode-se concluir que os indivíduos com retrocolite ulcerativa idiopática apresentavam níveis mais altos de IL-6 nos sítios com periodontite, o que pode indicar um importante papel dessa citocina no estabelecimento e progressão da doença periodontal nesses pacientes.<br>Our aim was to measure the levels of interleukin-6 in gingival crevicular fluid (GCF) from patients with periodontitis and inflammatory bowel disease (IBD), and compare with systemically healthy controls with periodontitis. Besides, was measured IL-6 level in serum. Fifteen patients with Crohns disease (CD, mean age 38.2 11.4 years), 15 with ulcerative colitis (RCUI, 45.0 10.5) and 15 controls (C, 42.1 7.8) participated in this study. Probing pocket depth (PPD), attachment loss (CAL), presence of plaque and presence of bleeding on probing, were assessed in six sites per tooth. In each subject, GCF from four sites with gingivitis (GP- PPD≤ 3mm and CAL ≤ 1mm) and from 4 sites with periodontitis (PP- PPD ≥ 5mm and CAL ≥ 3mm), on different teeth, were collected with filter strips. The serum of those patients was also collected. The IL-6 was analyzed in the Luminex. The total amount and the concentration of IL-6 in GCF was significantly higher in PP sites from RCUI than in controls (p=0.028 e p=0.044, respectively). The total amount of IL-6 was significantly higher in PP than GP sites in the DC group (p=0.028). In serum, IL-6 does not differ between groups. Therefore was concluded that subjects with ulcerative colitis showed higher levels of IL-6 in periodontitis sites, which might indicate an important role of this cytokine in the onset and progression of periodontal disease in such patients.
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Körner, Carolin. "Die Analyse der Inhibition des Monozyten chemotaktischen Proteins-1 (MCP-1) und der Stimulation durch MCP-1 auf die Koloniebildung und die Zytokinexpression von Plattenepithelkarzinomen der Kopf-Hals-Region im FLAVINO-Assay." Doctoral thesis, Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-166787.
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Das Monozyten chemotaktische Protein-1 (MCP-1) ist ein CC-Chemokin, das in seiner Rolle als Chemoattraktor auf Monozyten in der Genese von Malignomen eine wesentliche Rolle spielt. Dabei kann es sowohl zur lokalen Tumorabwehr als auch zur Tumorgenese, Tumor-angiogenese und Metastasierung beitragen. Die vorliegende Arbeit untersucht die MCP-1-Inhibition und die Stimulation durch MCP-1 auf die Koloniebildung und die Zytokinexpression von Plattenepithelkarzinomen der Kopf-Hals-Region (HNSCC) im FLAVINO-Assay. Dieser ist ein klonogener, qualitätskontrollierter Ex-vivo-Koloniebildungsassay, der an der Klinik für Hals-Nasen-Ohrenheilkunde der Universität Leipzig etabliert und patentiert wurde und unter flavinschützenden Bedingungen durchgeführt wird. Weiterhin wird die Eignung von MCP-1, Interleukin-6 (IL-6), Interleukin-8 (IL-8) und des Vascular endothelial growth factor (VEGF) als Biomarker in HNSCC, die mithilfe von ELISA in Seren und Kulturüberständen quantifiziert wurden, untersucht. Durch die Stimulation durch MCP-1 und dessen Blockade sowie durch in vivo tolerierbare Konzentrationen von Cisplatin, Docetaxel, Cilengitide und Temsirolimus wurde die Expression der untersuchten Zytokine in den Kulturüberständen der HNSCC unterschiedlich moduliert. Cisplatin und MCP-1 supprimierten die Koloniebildung signifikant, während unter Docetaxel und Temsirolimus eine insignifikante Reduktion und durch Cilengitide eine insignifikante Stimulation der Koloniebildung beobachtet wurde. Die MCP-1-Blockade durch einen Anti-MCP-1-Antikörper führte zu keiner signifikanten Modulation der Koloniebildung. MCP-1 und der Anti-MCP-1-Antikörper senkten die Zytokinexpression, während bis auf Cisplatin alle Zytostatika die Zytokinexpressionen steigerten. Bezüglich der kombinierten Testung der Zytostatika und der MCP-1-Blockade bzw. Stimulation unterschieden sich die Proben, sodass additive, synergistische und antagonistische Effekte resultierten. Da durch MCP-1 gesteuerte tumorassoziierte Makrophagen das Mikromilieu eines Tumors wesentlich beeinflussen, gebührt diesen ebenfalls eine besondere Aufmerksamkeit. In dieser Arbeit wurden unter MCP-1 antitumoröse Effekte beobachtet, sodass weitere klinische Testungen der antitumorösen Wirkung des MCP-1 auf HNSCC lohnenswert erscheinen. Die individuelle Chemoresponse-Testung kann dabei helfen, das biologisch heterogene Verhalten der HNSCC besser zu verstehen. In diesem Sinne wäre die klinische Validierung solcher Testsysteme wertvoll.