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1
Webb, Ginette Rachel. "Cytokines and cytokine receptors in osteoarthritis". Thesis, University of Bristol, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388158.
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2
Deller, Marc Christian. "Structural studies of cytokines and cytokine receptors". Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326028.
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3
Palmblad, Karin. "Cytokines and cytokine-directed intervention in experimental arthritis /". Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4589-6/.
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4
Affò, Silvia. "Cytokines and Cytokine-Receptors in the Pathogenesis of Alcoholic Hepatitis". Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/145435.
Testo completoAbstract (sommario):
By performing a translational study we identified a specific pattern of genes differentially regulated in patients with severe alcoholic hepatitis (AH). A functional analysis of the gene expression profile showed several pathways deregulated in AH, including cytokines- cytokine receptor interaction. Within cytokine-cytokine receptor interaction pathway, Fn14 has been identified as the only receptor belonging to TNF superfamily to be exclusively up-regulated in patients with AH, and its expression has been shown to be associated with severity of the disease and mortality. We observed that Fn14 is upregulated in experimental models of progenitor cell expansion and co-expressed with Ep-CAM in livers of patients with AH, suggesting that Fn14 may regulate ductular reaction expansion. Moreover, we showed that Fn14 hepatic expression is regulated by ethanol and pro-fibrogenic factors, suggesting that alcohol abuse together with fibrogenic mediators may be directly responsible for the induction of Fn14 expression in ALD.
Furthermore, transcriptome analysis identified CCL20 as the most up-regulated cytokine in the liver of patients with AH. Hepatic expression and serum levels of CCL20 have been found elevated in patients with AH and have been showed to be associated with key clinical features of the disease such as fibrosis, endotoxemia and short-term mortality. These data suggest that besides playing a role in AH pathogenesis, CCL20 may also be considered as a potential non-invasive biomarker. We found that CCL20 hepatic expression is up-regulated in acute, chronic and acute-on chronic experimental model of liver injury induced by carbon tetrachloride (CCl4) and lipopolysaccharide (LPS) and their combination, respectively. Macrophages and hepatic stellate cells have been identified as the main CCL20 producing cell types in experimental models of acute-on-chronic liver injury. Moreover, we have showed that CCL20 exerts pro-fibrogenic and pro-inflammatory and effects on primary human hepatic stellate cells and on macrophages, suggesting that CCL20 may participate in both hepatic fibrosis and inflammation
during liver disease in an autocrine and paracrine manner. Finally, we have found that CCL20 mediates LPS-induced liver injury by promoting hepatocellular apoptosis, expression of pro-inflammatory and pro-fibrogenic mediators and by enhancing macrophages and neutrophils infiltrate recruitment.
In conclusion, during this thesis we performed two studies leading to the identification of new potential targets for therapy in AH. The identification of Fn14 and CCL20 as new potential targets for therapy in AH and their correlations with key hallmarks of the disease such as ethanol consumption, fibrosis, progenitor cells expansion and endotoxemia underline the complexity of this disease and the crosstalk between many mediators that occurs in AH.
The data presented in this thesis suggest that cytokines and cytokine-receptor pathway could represent a new potential target for therapy in ALD; and also provide new important insights and a useful resource for the study of the pathogenesis of this disease.El consumo de alcohol es una de las causas más importantes de mortalidad que pueden prevenirse en nuestro país. La hepatitis alcohólica (HA) se caracteriza por un proceso de inflamación hepática (fundamentalmente por infiltración de células polimorfonucleares), esteatosis masiva hepática, fibrosis pericelular y daño hepatocelular. En la actualidad no existen tratamientos efectivos para el tratamiento de la HA y por esta razón, existe una clara necesidad de identificar nuevas dianas terapéuticas para tratar a estos pacientes en los diferentes estadios de la enfermedad (esteatosis, inflamación y/o fibrogénesis). El objetivo principal de esta tesis fue investigar nuevas dianas terapéuticas para el tratamiento de la HA. Para alcanzar dicho objetivo, realizamos estudios traslacionales que permitieran identificar marcadores biológicos alterados en muestras humanas procedentes de hígados de pacientes con HA para estudiar la función que tienen en el desarrollo de la enfermedad in vitro e in vivo en modelos animales de diferentes tipos de daño hepático y valorar si podrían considerarse como dianas terapéuticas. Mediante la performación de nuestros estudios, identificamos a la vía de citoquinas-receptores de citoquinas como una de las vías con el mayor número de genes diferentemente regulados en pacientes con HA con respecto a controles sanos. Estudios en muestras humanas y en modelos animales de daño hepático nos permitieron identificar al receptor de citoquinas Fn14 y a la citoquina CCL20 como importantes mediadores de la HA, correlacionados tanto con aspectos clínicos característicos así como con la gravedad de la enfermedad. La vía de citoquinas y receptores de citoquinas y, de manera específica Fn14 y CCL20 han sido identificados como novedosos mediadores implicados en la patogénesis de la HA y por lo tanto como potenciales dianas terapéuticas. Por lo tanto, gracias a la identificación de un patrón de los genes diferentemente regulados en la HA, nuestros datos proporcionan importantes resultados novedosos para el estudio de la patogénesis de la HA.
5
Ozaki, Akihiko. "Expression of cytokines and cytokine receptors in human Schwann cells". Kyoto University, 2008. http://hdl.handle.net/2433/135921.
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6
Croxford, J. Ludovic. "Gene therapy for experimental allergic encephalomyelitis by delivery of inhibitory cytokines or cytokine inhibitors". Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314201.
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7
Dossinger, Veronika. "Kleeblattpeptide und proinflammatorische Cytokine". [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=965165604.
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8
Turner, Martin John Charles. "Regulation of cytokine production". Thesis, Imperial College London, 1990. http://hdl.handle.net/10044/1/46588.
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9
Ventevogel, Melissa Samo. "Cytokine Modulation of Thymopoiesis". NCSU, 2008. http://www.lib.ncsu.edu/theses/available/etd-03182008-100350/.
Testo completoAbstract (sommario):
The thymus is an organ derived from embryonic endoderm and mesoderm differentiation. It is located above the heart and is made up of two compartments, the thymic epithelial space and the perivascular space. The thymic epithelial space consists of the cortex and the medulla, which is where T cell development, maturation and induction of self tolerance occur in a process known as thymopoiesis. The thymus is susceptible to chronic and acute stressors that result in thymic involution. A consequence of thymic involution is reduced thymopoiesis, which affects the generation of a diverse T cell repertoire and establishment of central T cell tolerance. Many thymosuppressive and thymostimulatory cytokines are involved in thymopoiesis and thymic involution. Keratinocyte growth factor and IL-7 are two cytokines that function in driving early thymic progenitor proliferation and T cell development, respectively. We hypothesized that IL-7 and Keratinocyte growth factor, delivered via recombinant adenovirus, can improve thymopoiesis and T cell reconstitution in mice in an endotoxin model of acute thymic atrophy. Analysis of thymus weight, cellularity, phenotype and TCR gene rearrangement showed moderate increases in thymic function with delivery of IL-7 or Keratinocyte growth factor versus control. Taken together, these data suggested that IL-7 and Keratinocyte growth factor, delivered via recombinant adenoviruses, have thymostimulatory effects on the thymus in normal thymus or settings of acute thymic atrophy and maybe beneficial for future development as therapeutics.
10
Jordan, William James. "Cytokine responses during alloreactivity". Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406452.
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Jit, Kresna Mark Surinder. "Modelling autocrine cytokine networks". Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.484417.
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12
Gianacopolos, A. K. "Cytokine regulated neutrophil function". Thesis, University of Liverpool, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.359012.
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13
Ghorayeb, Christine. "The regulation of human B cell effector cytokine profiles by exogenous T helper cell cytokines /". Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111556.
Testo completoAbstract (sommario):
The Bar-Or laboratory recently reported that human B cells from normal subjects can produce either pro-inflammatory (TNF-alpha; LT) or regulatory (IL-10) effector cytokines depending on their context of activation. It was of interest to investigate the change in B cell cytokine profiles from normal subjects when activated in the context of a Th1 pro-inflammatory environment or a Th2 anti-inflammatory environment. It was found that the B cell regulatory network of effector cytokines from normal subjects is significantly modulated depending on the local cytokine milieu. In addition, it was of interest to study how MS patients' B cell cytokine network would respond in a Th1 pro-inflammatory and a Th2 anti-inflammatory context. It was found that MS patients' B cell cytokine network was dysregulated compared to B cell responses from normal subjects. The findings define a novel regulatory network involving human B cells from normal subjects and point to a newly discovered abnormality in MS patients' B cells.
14
Daniels, Garry D. "Cloning and characterisation of cytokine and cytokine receptor genes in rainbow trout, Oncorhynchus mykiss". Thesis, University of Aberdeen, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265893.
Testo completoAbstract (sommario):
Convincing molecular evidence for the existence of both cytokines and their receptors in teleost fish is presented. TGF-β is present in O. mykiss encoding a 112 amino acid mature peptide. An integrin binding site (RGD) and a characteristic tetrabasic cleavage site (RKKR) are present, as is the TGF-β superfamily motif. The mature peptide has 9 conserved cysteine residues (8 of which occur in pairs) as well as two additional conserved TGF-β superfamily residues (Pro36 and Gly46). TGF-β exhibits a wide range tissue distribution including head-kidney macrophages, PBL, brain, gill and spleen tissue, and is encoded by a 2.5Kb mRNA. The trout TGF-β gene is spread over 7 exons, with an additional intron in exon 7 when compared to mammalian and avian models. Isolation of a partial sequence also reveals the presence of TGF-β in a cyprinid species. Phylogenetic analysis suggests trout TGF-β to cluster with mammalian TGF-β1 isoforms, and the avian (TGF-β4) and amphibian (TGF-β5) homologs. Neither TNF-α or TNF receptors were detected in O. mykiss at either the cellular or molecular level. The use of degenerate primers in PCR lead to the isolation of a partial sequence for O. mykiss MHC class I. A full length CXC-R gene of 1.6Kb isolated from O. mykiss displays approximately 65% identity to mammalian CXC-R4 receptors, exhibits the seven-transmembrane domain structure of the G-protein coupled receptors and a tissue-specific distribution. Characteristic superfamily motifs and a putative glycosylation site are present in the sequence. Along with the major features of the adaptive immune response such as the major histocompatibility complex (MHC), T-cell receptor (TCR) and immunoglobulin (Ig), cytokines are now shown to be present at the level of teleost fish.
15
Raccurt, Mireille. "L'hormone de croissance : une cytokine". Phd thesis, Ecole pratique des hautes études - EPHE PARIS, 2003. http://tel.archives-ouvertes.fr/tel-00069301.
Testo completoAbstract (sommario):
L'hormone de croissance (GH) est une hormone paradoxale. Historiquement reconnue comme responsable de la croissance post-natale, elle est actuellement considérée comme une véritable cytokine, synthétisée en de nombreux sites extra-hypophysaires et impliquée, lorsque dérégulée, dans les processus de tumorigénèse. Le travail présenté dans cette thèse a permis de caractériser et localiser par RT-PCR in situ, les cellules capables de synthétiser la GH dans le système immunitaire du fœtus et du rat adulte, puis dans les différents systèmes de prolifération cellulaire du carcinome canalaire mammaire humain montrant ainsi que la GH, par son action autocrine / paracrine est non seulement impliquée dans le développement embryonnaire mais participe à la progression tumorale. Nos travaux in vitro montrent que l'internalisation et la translocation nucléaire de la GH complexée à son récepteur sont indépendantes de l'activation de JAK2 « Janus Kinase 2 », cependant indispensable à son exportation hors du noyau. L'étude du système de régulation négative du signal induit par la GH nous a permis de mettre en évidence une surexpression de la protéine CIS « Cytokine-Inducible SH2-containing protein », dans les zones de prolifération tumorale des différents carcinomes étudiés et dans 8 lignées tumorales mammaires. La surexpression de CIS, in vitro, inhibe la voie de signalisation JAK/STAT « Signal Transducer and Activator of Transcription » et active la voie des MAPK « Mitogen Activated Protein Kinases ». Nous avons pour finir, corrélé l'activation prédominante de CIS à la synthèse de GH « autocrine » dans les cellules tumorales mammaires MCF-hGH. La localisation tant nucléaire que cytoplasmique de la GH et de toutes les molécules informatives laisse entrevoir des mécanismes de régulation encore inconnus. Les travaux futurs tenteront de répondre à la question maintenant cruciale : la GH, hormone de jouvence ou véritable oncogène ?
16
Paton, Tara E. "Cytokine mediated downregulation of CYP1A1". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1996. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/mq24985.pdf.
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17
Brown, Cheryl Yvette. "Regulation of cytokine mRNA stabilty /". Title page, contents and summary only, 1996. http://web4.library.adelaide.edu.au/theses/09PH/09phb877.pdf.
Testo completoAbstract (sommario):
Thesis (Ph. D.)--University of Adelaide, Dept. of Microbiology and Immunology and Div. of Human Immunology, Hanson Centre for Cancer Research, Institute of Medical and Veterinary Science, 1996.Copies of author's previously published works inserted. Includes bibliographical references.
18
Tam, Wai Keung. "Cytokine gene expression in glomerulonephritis". Thesis, Imperial College London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363081.
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19
Zghebeh, Helena. "Cytokine polymorphisms in pre-eclampsia". Thesis, University of Leeds, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.511158.
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20
Formela, Laura Janina. "Cytokine signalling in acute pancreatitis". Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250413.
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21
Cookson, Sharon. "Cytokine genes in liver immunopathology". Thesis, King's College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271515.
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22
Zisakis, Athanasios. "Cytokine secretion in glioblastoma patients". Thesis, University of Central Lancashire, 2008. http://clok.uclan.ac.uk/19220/.
Testo completoAbstract (sommario):
Gliomas are the most common primary tumours of the central nervous system with a lethality rate approaching 80% in the first year of glioblastoma diagnosis. Their highly invasive nature renders local therapies such as surgery and radiation ineffective; whereas novel approaches such as immunotherapy are being actively studied as possible adjuncts in the treatment of patients with malignant gliomas. A number of factors have been proposed to play a role in glioma immune escape, including their poor immunogenicity since they do not express specific glioma antigens; their location within the CNS, which is considered to be an immune-privileged organ and some indications that glioma cells are capable of releasing various immunosuppressive cytokines, which inhibit the cytotoxic function of T cells. Cytokines are multifunctional pleiotropic proteins, which are involved in intercellular communication and cellular activation, and they may exert their effects in the CNS both directly and indirectly. Since they may originate either from peripheral immune organs, and cross the blood-brain barrier or they may be produced by the neuronal cells within the CNS, their properties are both immunoregulatory and neuromodulatory. This thesis investigated gliomas for the expression of cytokines and implicated their expression in the malignancy and the angiogenesis of the tumours. Cytokine secretion was evaluated from isolated peripheral blood mononuclear cells (PBMCs) of 33 patients with malignant gliomas (grade IV) immediately before surgery, in parallel with a control group of 23 age-matched individuals, and in 5 primary glioma cell cultures using the sensitive ELISPOT methodology. Thi cytokines tumour necrosis factor (TNF-a) and interferon (IFN7) were markedly reduced compared to control levels (P=0.01 and P < 0.001, respectively). In contrast, Th2 interleukins IL-(4) and IL-(10) were strongly expressed in both peripheral lymphocytes and glioma cell cultures (P < 0.05 and P < 0.001 respectively). Immunohistochemical localisation of IL-6, IL-8, COX, IL-lO, VEGF (vascular endothelial growth factor) and CD34 expression levels was performed in formalin-fixed paraffin-embedded tissue sections taken from 23 patients. Microvessels highlighted by means of anti-CD34 irnmunohistochemistry were enumerated with computer assisted image analysis. IL-6 was identified immunohistochemically in all specimens and showed an elevation in expression as necrosis grade increased (p=O.00S). IL-6 was also increased as the histological grade of the tumour increased (p0.020). IL-S expression was detected in all cases of gliomas with a mean of 19.5% of the cells. Expression was not related to either necrosis grade or increase in tumour grade. COX immunoreactivity was detected in all cases with an average of 29.1% positive cells. However, COX immunoreactivity was not significantly correlated with either necrosis or tumour grade. VEGF immunoreactivity occurred in 58.3% of cells and demonstrated a positive correlation with tumour grade (pzr0.035). The expression level of IL-10 was low both in terms of staining intensity and percentage of positive cells, and did not correlate with either necrosis or histological grade. CD34 immunoreactivity indicated that vascular volumetric parameters were not affected by either tumour or by necrosis grade. The expression of soluble CD95 as measured using a specific ELISA was not significantly (p > 0.05) reduced in the serum of 43 glioma patients compared to normal levels. In conclusion, these results indicate that patients harbouring malignant gliomas exhibit a broad suppression of cell-mediated immunity possibly due to the marked dysregulation in their cytokinetic profile. Glial tumours seem to induce a Thi (stimulatory) to Th2-type (inhibitory) cytokine shift which further supports humoral immunity at the expense of cell-mediated immune responses, contributing to the inefficient anti-tumour responses generated in these patients.
23
Kurth, Ingo. "Untersuchungen zur Zytokinbindung und Rezeptoraktivierung des Signaltransduktors gp130 durch seine Liganden IL-6 und IL-11". [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=968740758.
Testo completo
24
Derouet, Damien. "Activation des récepteurs de cytokines de la famille de l'interleukine-6". Thesis, Angers, 2018. http://www.theses.fr/2018ANGE0006.
Testo completoAbstract (sommario):
Les cytokines de la famille de l’IL-6 possèdent comme caractéristique commune la capacité à recruter une chaine réceptrice membranaire nommée gp130. Au début de notre étude, cette famille comptait 8 membres : IL-6 et son homologue viral (vIL-6), IL-11, LIF, OSM, CNTF, CT-1 et CLC. Depuis, cette famille s’est enrichie de trois nouveaux membres, NP, IL-27 et IL-31. Ces cytokines sont essentielles au développement (LIF et CT-1) ou sont impliquées dans l’hématopoïèse, les réponses immunitaires et l’inflammation (IL-6, IL-11, IL-27, IL-31 et OSM) alors que d’autres agissent plus particulièrement au niveau du système nerveux, comme NP, CLC et CNTF. Le premier axe de recherche de ma thèse a porté sur l’identification d’un nouveau membre de cette famille,la neuropoïétine (NP), et plus précisément sur la caractérisation de son profil d’expression tissulaire et l’identification de son récepteur, des principales voies de signalisation intracellulaire induites ainsi que ses fonctions biologiques. Le deuxième axe de recherche a consisté à étudier la capacité de CLC à se comporter comme un ligand alternatif du récepteur tripartite au CNTF, impliqué dans le développement neuronal. Pour cela, nous avons mis en évidence la présence de la cytokine CLC et de ses partenaires de sécrétion, dans l’environnement des motoneurones lors du développement embryonnaire chez la souris. Enfin, le dernier axe de recherche s’est focalisé sur le rôle des états de glycosylation de CLC sur la sécrétion des cytokines composites CLC/CLF et CLC/solCNTFRαMembers of the interleukin 6 (IL-6) cytokine family share a common characteristic, the capacity to signal via thegp130 subunit receptor. This family contains 8 members : IL-6 and its viral counterpart (vIL-6), IL-11, LIF, OSM, CNTF, CT-1 and CLC. This family has been more recently enriched with three new members, neuropoietin (NP), IL-27 and IL-31. These proteins are involved in development (LIF and CT-1), in hematopoiesis, immune responses and inflammation, such as IL-6, IL -11, IL-27, IL-31 and OSMor act in the nervous system (NP, CLC and CNTF). My first research work was focused on the identification of a new member of this family, neuropoietin. More specifically, this study allowed determining its tissue expression profile, its complex receptor and the signaling pathways induced, and its biological functions. A second research project was focused on determining whether CLC may constitute an alternative ligand for the CNTF receptor, involved in the neuronal development. We have evidenced the presence of CLC and its secretory partners, in the environment of motoneurons during embryonic development in mice. Finally, I have evaluated the role of the glycosylationstates of CLC on the secretion of the composite cytokines CLC/CLF and CLC/solCNTFR
25
Piccirillo, Ciriaco A. "Cytokine gene therapy of autoimmune disease". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0023/NQ50237.pdf.
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26
Testar, Jodie. "Signalling pathways regulating inflammatory cytokine expression". Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.484431.
Testo completoAbstract (sommario):
My research has strived to understand two different aspects of immune cell response to stimuli: i) cross talk between innate and adaptive immune responses; ii) regulation of inflammatory signalling by a novel phosphoprotein, Arhgef101. Canonical and non-canonical NFκB signalling pathways have been described to date, each inducing a distinct gene expression profile. Current understanding indicates the canonical being mainly involved in innate- and non-canonical being mostly involved in adaptive immunity. Using a T cell hybridoma model, I established that chronic activation of the canonical pathway by TNFα led to up-regulation of components of the non-canonical pathway, specifically Re1B and p100. Hypothesising that cells exposed chronically to TNFa would then have enhanced non-canonical activation propagating the inflammatory response, CD27 was identified as a model system for activating the non-canonical NFκB pathway. In spite of exhaustive attempts with this system and other receptor systems, none were found to be capable of inducing robust and reproducible non-canonical NFκB activation. We have identified a novel phosphorylation designated Arhgef101. Arhgef101 was found to undergo tyrosine phosphorylation in the murine macrophage cell line, RAW 264.1, after LPS stimulation. Murine tissue screening for Arhgef101 RNA showed ubiquitous expression. No compartmental, membrane or actin filament associations were observed. Overexpression of Arhgef101 in RAW cells resulted in overproduction of TNFa but not IL-6 after TLR4 stimulation, when compared to untransfected cells. Overexpression in the murine fibroblast cell line, NIH 3T3, amplified both IL6 and KC production in response to IL1 and LPS. Primary-transcript quantitative PCR suggests a potential transcriptional regulatory role for Arhgef101. With no detectable differences in the major signalling pathway NFκB, ERK, JNK, or p38 MAPK these data implicate Arhgef101 as a potential signalling adaptor involved in an, as yet, unidentified signalling pathway.
27
Gandhi, Hetvi. "Early events in cytokine receptor signaling". Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-135614.
Testo completoAbstract (sommario):
Ligand-activated signal transduction is a process critical to cell survival and function as it serves as a means of communication between the cells and their environment. Endocytosis is generally thought to down-regulate incoming signals by reducing the surface availability of receptors. However, increasing evidence in many systems suggests a notion which is referred to as the „signalling endosome" hypothesis - that endocytosis can also actively contribute to signalling apart from clearance of activated receptors and thereby attenuation of signalling. The functional aspect of signalling endosomes has been well-characterized in several pathways including RTK and TGF-β signalling. There are, however, various other signalling pathways where the active mechanism of endocytotic regulation is yet to be understood.
In this study, we probe this aspect in the cytokine signalling system, where the receptors are known to internalize but the significance of such internalization and precise mechanism is unclear. My thesis aims to elucidate the function and molecular details of internalization of cytokine receptor using interleukin-4 receptor (IL-4R) signalling as a model. IL-4 and IL-13 ligands can induce assembly of three distinct complexes: IL4 induced IL-4Rα – IL-2Rγ (type I), IL-4 induced IL-4Rα – IL-13Rα1 (type II) or the IL-13 induced IL-13Rα1-IL-4Rα (type II). The formation of any of these complexes triggers signalling through the JAK/STAT pathway. However, models of how the oligomerization of the transmembrane receptors and activation takes place are very diverse and lack a clear molecular and biophysical understanding of the underlying receptor dynamics.
Previous results of the lab had shown that the affinities between subunits are low, precluding complex formation at the plasma membrane at physiological concentrations. In addition, IL-4R subunits localize in to endosomal structures adjacent to the plasma membrane. It had already been shown that the shared IL-4R subunit IL-2Rγ is internalized by a specific, actin dependent, Rac1/Pak1 regulated endocytosis route in the IL-2 context. We could show that pharmacological suppression of this endocytosis pathway also prevented IL-4 induced JAK/STAT signalling, placing endocytosis upstream of signalling.
Here I show using immuno-EM techniques that these endosomal structures are multivesicular bodies. Importantly, I could show that receptor subunits are highly enriched in the limiting membrane of these endosomes relative to the adjacent plasma membrane. Using quantitative loading assays I could furthermore demonstrate that this enrichment is achieved by constitutive internalization of receptors from the cell surface into cortical endosomes. The trafficking kinetics of the receptor subunits is independent of ligand occupancy. Pharmacological inhibition shows that receptors and ligand traffic via the previously identified Rac1/Pak1 pathway. Finally, Vav2 was identified as a candidate Guanine Exchange Factor (GEF) that may regulate Rac1 activity and thereby control the actin polymerization cascade driving IL-4R endocytosis. Immunoprecipitations showed that Vav2 interacts both with the cytoplasmic tail region of the receptors and the receptor associated 2 kinase JAK3. Vav2 may thus couple the receptor/JAK complexes to the Rac1/Pak1 mediated endocytosis route.
Taken together, our results suggests that stable „signalling endosomes‟ adjacent to the plasma membrane act as enrichment centres, where ligand and receptor concentrations are locally increased by constitutive trafficking. The confined environment of the endosome then compensates for the weak affinities between the ligand and receptor and facilitates ligand-mediated receptor dimerization. Importantly, overexpression of both type II IL-4R subunits renders signal transduction resistant to endocytosis inhibition, strongly suggesting that the critical factor effecting signalling is sufficient concentration, which the endosomes facilitate achieving. The endosomes are thus dispensable as signalling scaffolds when the receptors are in sufficient concentration, where activated receptors could interact with downstream pathway components.
Endocytosis thus provides a crucial means for the signalling process to overcome the thermodynamic hurdles for receptor oligomerization. In conclusion, our data propose a novel, purely thermodynamic role of endosomes in regulating cytokine receptor signalling not seen in any other signalling pathway.
28
Li, Jiejin. "Biophysical studies of cytokine receptor interactions". Thesis, University of Oxford, 2000. http://ora.ox.ac.uk/objects/uuid:a5dbcc9a-b73a-495a-8cf6-60ef064da0da.
Testo completoAbstract (sommario):
The IL-6 family of cytokines includes IL-6, ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), oncostatin M (OSM), cardiotrophin-1, and IL-11. Functioning in a pleiotropic and redundant manner, these cytokines play an important role in the regulation of complex cellular processes such as gene activation, proliferation and differentiation, by signalling through homo- or heterodimers of gp130. This thesis describes the characterization of the interactions between the cytokine oncostatin M (OSM) and the cytokine-binding homology region (CHR) of its receptor gp130. Three forms of OSM were expressed, the native form and two truncated forms. Both mutations were obtained by C-terminal truncation. The first, OSM185, has an 11 amino residue deletion and the second, OSM187, has a 9-residue deletion. A variety of biophysical techniques were applied to investigate the complex. Analytical ultra-centrifugation (AUC), surface Plasma Resonance (SPR) and isothermal titration calorimetry (ITC) studies indicated that the purified proteins were stable in monomeric form and can form a 1:1 complex with affinity in the 0.1 μM range. One of the C-terminal truncated forms, the 187 residues version, showed higher stability than the native OSM (196 residues), but still demonstrated similar binding properties to the gp130-CHR. A 15N and 13C double-labelled OSM187 sample was produced for NMR studies. Due to the size of these two proteins, OSM187 (21.5 kDa) and gp130-CHR (25.2 kDa), the NMR studies of the complex are challenging. Applying the TROSY technique, data were obtained from the labelled OSM187 when it is in complex with gp130-CHR. The data could be compared with the free form OSM187 and several shifted peaks were detected. The binding site mapping work has just begun. The characterized binding properties and methods established for sample preparation provide a solid starting point for later studies. The thesis also contains an exploratory study of interactions between interleukin-2 (IL-2) and the IL-2 receptor β chain.
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Gavalas, Nikolaos. "Lipid anchored truncated cytokine receptor antagonists". Thesis, University of Sheffield, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419273.
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30
Stevens, Michael. "Mathematical modelling of inflammatory cytokine networks". Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404767.
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31
Bradding, Peter. "Cytokine expression in allergic mucosal inflammation". Thesis, University of Southampton, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295929.
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32
Emsley, Hedley C. A. "Inflammation and cytokine regulation in stroke". Thesis, University of Manchester, 2004. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:192689.
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33
Castro, Mike. "Cytokine Modulation of Cardiomyocyte-Macrophage Interaction". Wright State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=wright157858331333014.
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34
Baugh, John Andrew. "Differential regulation of monocyte cytokine release". Thesis, University of Bath, 1999. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285313.
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35
Elkarim, Rihab A. "Potential role of anti-cytokine autoantibodies in the regulation of cytokine responses in infections and autoimmune diseases /". Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3774-5/.
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36
Chevalier, Anne Sophie. "Utilisation thérapeutique du G-CSF et du GM-CSF en hématologie". Paris 5, 1993. http://www.theses.fr/1993PA05P248.
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37
Zeidan, Mohamad Jamal. "An Exploration of Non-Antineutrophil Cytoplasmic Antibodies Serum Biomarkers in Systemic Vasculitis : An Investigation of Behçet’s Disease". Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066161/document.
Testo completoAbstract (sommario):
Les hypothèses retraçant les mécanismes physiopathologiques de la maladie de Behçet (MB), une vascularite inflammatoire non liée aux anticorps anti-cytoplasme des polynucléaires neutrophiles (ANCA), sont multiples. Cette étude propose une compilation exhaustive des mécanismes immunopathologiques décrits dans la littérature contemporaine, et fournit un résumé détaillé des aspects cliniques de la maladie et de ses différents traitements. Cette étude inclut également une analyse statistique de 20 signatures de protéines proposées comme biomarqueurs potentiels de la MB. Vingt-deux patients avec une MB active (MBA) et 46 patients avec une MB inactive (MBI), répondant aux critères de l’International Criteria for Behçet Disease (2013), ainsi que 47 donneurs sains (DR) et 98 patients subissant une angiographie coronaire (AC) ont fourni des échantillons de sérums pour une étude de dosage multiplex. Les résultats indiquent que les protéines sériques ICAM-1, SAA, THBD, et VCAM-1 jouent un rôle essentiel dans la différenciation entre les patients MB et les DR. De même, Caldesmon, Clusterin, CRP, IL-8, SELP et SICMA3 permettent un tri entre les patients MB et AC. Les modèles de signatures des biomarqueurs proposés dans cette étude et qui séparent entre les patients atteints par la MB, les DR et / ou les AC, représentent une nouvelle piste pour le développement de tests sériques pour la MB, avec une sensibilité et une spécificité élevées. Ceci peut éventuellement compléter les outils de diagnostic clinique établis. Ces résultats apportent une contribution significative à l’interprétation actuelle de la pathogénie de la MB en tant que vascularite auto-immune non-ANCA. Cette enquête fournit un bilan à la fois qualitatif et quantitatif aux cliniciens et aux chercheurs dans ce domaineHypotheses concerning the specific pathophysiological mechanisms of Behçet’s Disease (BD), a non-antineutrophil cytoplasmic antibodies (ANCA) inflammatory vasculitis, are numerous. This study offers an exhaustive review of the disease in an attempt to recap the immunopathological pathways described by extant literature, and provides a detailed summary of the clinical aspects of, and treatment options for the disease. In addition, this investigation completed a statistical analysis of 20 protein signatures that were proposed as potential biomarkers for BD. Twenty-two patients with active BD (BDA) and 46 patients with inactive BD (BDI) fulfilling the International Criteria for Behçet's Disease, 47 healthy donors (HD), and 98 coronary angiography patients (CA) provided serum samples for a multiplex assay study. Findings indicate that serum proteins ICAM-1, SAA, THBD, and VCAM-1 play a significant role in differentiating BD patients from HD. Likewise, Caldesmon, Clusterin, CRP, IL-8, SELP, and sICAM-3 segregate between BD and CA. The biomarker predictive models proposed in this study that segregate between BD, HD, and / or CA represent a significant avenue for the development of sera testing specific to BD with a high level of sensitivity and specificity. This may serve as a supplement to established clinical diagnostic tools. These results represent a noteworthy complement to the current interpretation of the pathogenesis of BD as an autoimmune non-ANCA vasculitis. This investigation provides expert clinicians and researchers with both qualitative and quantitative outcomes
38
Bertot, Laëtitia. "Le rôle des protéines courbant les membranes dans l’endocytose indépendante de la clathrine suivie par le récepteur de l’interleukine 2". Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS570/document.
Testo completoAbstract (sommario):
L’endocytose permet l’internalisation d’éléments présents dans le milieu extracellulaire tels que les nutriments. Ce processus prend place dans la membrane plasmique. Les courbures de la membrane jouent un rôle essentiel dans l’endocytose pour générer une invagination initiale, un puits, puis une vésicule qui se sépare ensuite de la membrane plasmique pour fusionner avec les compartiments intracellulaires. Il existe plusieurs voies d’endocytose qui peuvent être classées selon des critères tels que la taille des vésicules produites, la médiation par un récepteur ou la présence d’un manteau recouvrant les vésicules. La voie d’endocytose la mieux caractérisée est celle dépendante de la clathrine. Mon laboratoire d’accueil travaille sur l’entrée du récepteur de l’interleukine 2 (IL-2R). Ce récepteur peut entrer de façon constitutive ou induite en présence de son ligand l’IL-2. Les deux voies sont indépendantes de la clathrine. Lors de mon arrivée dans le laboratoire, ces voies étaient encore peu caractérisées, notamment les facteurs induisant les courbures membranaires restaient à identifier. Ces facteurs doivent être particulièrement impliqués car les vésicules contenant l’IL-2R sont dépourvues de manteaux. Un crible par interférence à ARN, réalisé avant mon arrivée avait permis de proposer des protéines candidates pouvant courber les membranes. La première partie de ma thèse a consisté à confirmer l’importance de certaines protéines issues de ce crible puis à étudier leurs rôles dans la voie constitutive de l’IL-2R. Parmi ces protéines confirmées, deux familles de facteurs étaient particulièrement intéressantes pour leur capacité à courber les membranes, les phospholipases D et les endophilines. Ces dernières ont permis d’identifier une nouvelle voie d’entrée nommée « Fast Endophilin Mediated Endocytosis » FEME dans laquelle l’endophiline joue un rôle essentiel et qui est empruntée par de nombreux récepteurs transmettant le signal. La voie FEME partage plusieurs facteurs communs avec la voie d’endocytose induite de l’IL-2R. Pour finir, mes travaux de thèse ont porté sur l’orchestration de l’endophiline et de la dynamine dans la voie d’endocytose constitutive de l’IL-2R. Ces deux facteurs sont impliqués en fin d’endocytose, pour scinder les vésicules de la membrane plasmique. Cependant, ces deux protéines n’ont pas la même orchestration. Nos travaux montrent une action distincte de l’endophiline et de la dynamine dans les voies d’endocytose dépendante et indépendante de la clathrineEndocytosis allows the uptake of elements from the extracellular fluid such as nutriments. This process takes place at the plasma membrane. The membrane curvatures play an important role in endocytosis for the production of initial invagination to form a pit that will be then separate from the plasma membrane and will go to the intracellular compartments. Several routes of endocytosis exist and can be classified depending on vesicles size formed, receptor mediated endocytosis or coat on vesicles. The well-known characterized endocytosis pathway is the clathrin mediated one. My lab is working on interleukin 2 receptor (IL-2R) entry. This receptor can enter either constitutively or upon induction by the ligand IL-2. Both uptake pathways are independent of clathrin. When I arrived in the lab, those pathways were still under characterization, in particular the factors inducing the membrane curvature. Their role should be important since IL-2R containing vesicles are coated free. A small interfering RNA screen performed before my phD, allowed to identify new candidates. The first part of my thesis was to verify the involvement of some of them in the IL-2R constitutive pathway and then to study their role in this pathway. Among them, 2 families of proteins were particularly interesting as they can curve membranes, phospholipases D and endophilins. The endophilin allowed the discovery of a new route called “Fast Endophilin Mediated Endocytosis” (FEME) in which it plays an essential role and which is used by numerous receptors that transmit signal. The FEME pathway shares several factors that are common with the IL-2 induced endocytosis pathway. Then, I conducted a work on the orchestration of endophilin and dynamin during the constitutive IL-2R endocytosis. Both factors are recruited at the end of the mechanism, to separate the vesicles from the plasma membrane. However, both proteins do not have the same orchestration. Our works show a distinct action of endophilin and dynamin in clathrin dependent and independent endocytosis
39
Cebo, Christelle. "Activité lectinique des cytokines humaines : implications dans les voies de transduction lymphocytaires et modélisation de l'interaction cytokine-ligand". Lille 1, 2001. https://pepite-depot.univ-lille.fr/RESTREINT/Th_Num/2001/50376-2001-145.pdf.
Testo completo
40
Hamedi, Mojgan. "The expression of Suppressor of Cytokine Signalling (SOCS), JAK-STAT signalling pathway and cytokine profile in Behçet's disease". Thesis, Queen Mary, University of London, 2013. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8557.
Testo completoAbstract (sommario):
Behçet’s disease (BD) is a chronic, multi systemic, recurrent vasculitis disease of unknown aetiology. The clinical manifestations are composed of relapsing episodes of recurrent oral ulcers, uveitis, skin lesions and genital ulcers along with musculoskeletal and neurological involvement. Pro-inflammatory cytokines are a key feature of the disease but the triggers for their induction are not well understood and/or controversial. Many cytokines (including IFNγ, IL-12, IL-23, IL-10 and IL-6) activate the JAK-STAT signalling pathway which is negatively regulated by Suppressor of Cytokine Signalling (SOCS) proteins. Therefore, it was hypothesised that SOCS proteins may be dysregulated in BD. The expression of SOCS 1-3 mRNA and protein was studied in peripheral blood mononuclear cells (PBMCs), Neutrophils and buccal mucosal cells (BMC) of BD patients and compared with healthy controls (HC) and recurrent aphthous stomatitis (RAS) patients. SOCS 1 and 3 were significantly upregulated in PBMCs of BD patients compared with HC (p=0.0149; p=0.0007) and there were subtle differences between expression in relapsed and symptom free BD (quiet BD). SOCS1 and SOCS 3 also significantly upregulated in BMC from oral ulcers of BD compared with HC (both at p=0.0001). Cytokines were examined in serum, saliva and culture supernatants from stimulated PBMCs. IL-6 were significantly upregulated in the saliva of relapsed BD patients compared with HC (p=0.0104) and the capacity for IL-10 secretion from BD was compromised. Phosphorylation of STATs, transcription factors RORγt, T-bet and 48 protein kinases were investigated using a novel PhosphFlow method and by microarray analysis. STATs were upregulated in BD and seven novel kinase proteins showed differential phosphorylation in BD. Conclusion: SOCS 1-3 expression has changed in BD patients with differences in PBMC and Neutrophil expression between the SOCS proteins. Phosphorylation of STATs and several kinases show up-regulation in BD and seven kinases with altered phosphorylation states in BD were identified as novel targets for future investigation.
41
Emtage, Peter Campbell Reynold. "Cytokine therapy of cancer by gene transfer". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0007/NQ42845.pdf.
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42
Boström, Müssener Åsa. "Cytokine regulation in rodents with experimental arthritis /". Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-2862-2.
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43
Radford-Smith, Graham Lindsay. "Cytokine gene expression in inflammatory bowel disease". Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296991.
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44
Paterson, Alison M. "Tolerance induction by cytokine-modulated dendritic cells". Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424869.
Testo completo
45
Atan, Deniz. "Cytokine gene polymorphism in non-infectious uveitis". Thesis, University of Bristol, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492470.
Testo completoAbstract (sommario):
Non-infectious uveitis is a blinding intraocular inflammatory disorder with an autoimmune pathogenesis. Like other autoimmune diseases, uveitis has multifactorial and polygenic aetiology. The results of this study have shown that polymorphisms of the ILIO and TNF genes influence the susceptibility and seventy of uveitis. These polymorphisms were either known to correlate with altered transcription levels, or linked with other polymorphisms positioned within regulatory conserved non-coding sequences. Thus the identification of specific genetic variants that confer susceptibility or resistance to uveitis has provided insights into the pathogenesis of uveitis, and might allow the prediction of patients who will have aggressive disease to allow tailoring of treatment to the individual.
46
Tannahill, G. M. "The role of SOCS2 in cytokine signalling". Thesis, Queen's University Belfast, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419408.
Testo completo
47
Magee, Gerald Damian. "Anti-cytokine strategies for gram-negative sepsis". Thesis, Queen's University Belfast, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318958.
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48
Estcourt, Claudia Simone. "Investigation of cytokine dysregulation in HIV infection". Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245087.
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49
Reynard, Mark. "Cytokine gene polymorphisms and their clinical relevance". Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404568.
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50
Synek, Miroslav. "Death in asthma : inflammatory and cytokine mechanisms". Thesis, University of Southampton, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296244.
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