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Rees, Louisa Elizabeth Natasha. "The regulation of interleukin-10". Thesis, University of Bristol, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322627.
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Schmid-Lossberg, Juliette. "Nachweis von Interleukin-1α, Interleukin-1ß, Interleukin-5 und Interleukin-10 im vaginalen Abstrich von gesunden Frauen". Diss., lmu, 2010. http://nbn-resolving.de/urn:nbn:de:bvb:19-114787.
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Powell, Mark Jason. "Gene regulation of murine interleukin -10". Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299106.
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Crawley, Esther Madeleine. "Interleukin 10 in juvenile idiopathic arthritis". Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249187.
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Forrester, Megan Amy. "Identification of interleukin-10 producing cells specific for Epstein-Barr virus latent membrane protein 1 and the involvement of interleukin-27 in their induction". Thesis, University of Aberdeen, 2011. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=167956.
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During latent Epstein-Barr virus (EBV) infection, the T helper cell response to the EBV latent membrane protein (LMP)1 is dominated by the production of IL-10, but by IFN- γ during acute EBV infection. The purpose of this thesis was to develop methods for the enumeration and characterisation of the IL-10 producing CD4+ T cells that respond to peptides of the EBV protein LMP1, and to investigate the possible involvement of IL-27 in the development of these cells. It was found that some human donors have very high concentrations of IL-27 within serum, which is not dependent on EBV infection status but demonstrates relatively low heritability. The addition of IL-27 to cultures of human T cells did not induce IL-10 but the production of IL-17 was inhibited. To identify and characterise LMP1 responsive cells I used CD154 as a marker of activated T cells. Having optimised the methodology, 14 donors of known EBV serostatus were tested for activated IL-10 producing cells after culturing peripheral blood mononuclear cells with LMP1 peptides. However in most cases the frequency of CD4+ lymphocytes upregulating CD154 and IL-10 in response to LMP1 peptides was below the assay’s sensitivity. When the CD154+IL-10+ CD4+ cells were stained for T helper cell subset markers they were positive for every marker and isotype control, suggesting that the cells were non-specifically binding labelled antibody. Both single positive CD154+ and single positive IL-10+CD4+ cells were also present in response to LMP1, but again typically at frequencies below the level of sensitivity for this assay. The conclusions of the work are that IL-27 responses are heterogeneous, but unlikely to play an important role in the induction of IL-10+ T cells in EBV infection. The frequency of LMP1 responsive T cells is very low (<0.08%) in most donors.
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Dohmen, Klaus Malte. "Die kritische Rolle von Interleukin-10 bei der Induktion nasaler Toleranz in der experimentellen Autoimmun-Myokarditis (EAM)". [S.l. : s.n.], 2007. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-58242.
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Walter, Claudia. "Bestimmung der Zytokine Interleukin-1ra, Interleukin-6, Interleukin-10 und Interleukin-12 im Vaginalsekret bei Frauen mit Bakterieller Vaginose". Diss., lmu, 2004. http://nbn-resolving.de/urn:nbn:de:bvb:19-28461.
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Capper, Emma Rachel. "The human interleukin-10 and interleukin-10 receptor system : molecular & genetic analysis of SLE and recurrent miscarriage". Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424695.
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Clarke, Christopher Jeremy Paul. "Molecular mechanisms of the anti-inflammatory cytokines interleukin-4 and interleukin-10". Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285172.
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Rempel, Julia D. "Interleukin-12 and interleukin-10 regulation of antibody responses upon protein antigen immunization". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ41623.pdf.
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Müller, Riccarda [Verfasser]. "Effekte einer Interleukin-10 Überexpression in humanen Gelenkchondrozyten und Interaktion von Interleukin-10 mit Tumor Nekrose Faktor-α / Riccarda Müller". Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2009. http://d-nb.info/1027813623/34.
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Schardt, Victor. "Vergleichende Untersuchungen zur Hefepilzbesiedelung von Mundhöhle und Vagina und Bestimmung von Interleukin-4, Interleukin-10 und Interleukin-12". Diss., lmu, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-155152.
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Leppert, Kyle McDonald McMurray Robert G. "The effect of glycogen depletion on responses of interleukin-1beta, interleukin-6, and interleukin-10 to maximal exercise". Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2009. http://dc.lib.unc.edu/u?/etd,2599.
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Thesis (M.A.)--University of North Carolina at Chapel Hill, 2009.Title from electronic title page (viewed Oct. 5, 2009). "... in partial fulfillment of the requirement for the degree of Master of Arts in the Department of Exercise and Sport Science Exercise Physiology." Discipline: Exercise and Sports Science; Department/School: Exercise and Sport Science.
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Strong, Victoria. "Modulation of dendritic cell function by interleukin-10". Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393790.
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Clutton, Genevieve Tyndale. "HIV-specific interleukin-10 responses and immune modulation". Thesis, University of Oxford, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.589623.
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Interleukin-l0 (IL-10) helps to limit the duration of potentially harmful inflammatory responses but has also been implicated in the persistence of a number of chronic viral infections. This thesis aimed to investigate the phenotype and function of mv -specific IL-l0-producing cells in chronic HIV-I infection, and the effect of IL-10 blockade on responses to candidate HIV -I vaccines. A cytokine capture assay was used to determine the HIV -specific cellular sources of IL- 10 in PBMC from 55 chronically infected individuals. A rare subset of CD8+ T cells was found to be the major HIV -I Gag-specific IL-10-producing population; these cells were restricted to ART-naive individuals and did not express the regulatory T cell markers CD25 or FoxP3 but could co-express IFN-y. A proportion of the population (median 48% and 9% respectively) expressed the P7 chain of the gut-homing integrin a4p7 and the chemokine receptor CXCR3, which mediates lymphocyte migration to sites of inflammation. Experimental depletion of Gag-specific IL-10+ CD8+ T cells did not affect T cell activation, or the production of cytokines such as IL-2 or IFN-y during short-term culture. However, depletion was associated with a significant increase in CD38 expression on CDI4+ monocytes, a trend towards increased HLA-DR expression on the same cells, and a significant increase in the concentration of the pro-inflammatory cytokine IL-6 in culture supernatants. There was also a significant increase in the number of HIV-infected (p24 antigen+) CD4+ T cells in cultures depleted of Gag- specific IL-10+ CD8+ T cells after 3 days, indicating that this population may contribute to control of viral replication. In order to determine the effect of IL-10 blockade on vaccine immunogenicity, IL-10R blocking antibody was administered to BALB/c mice prior to immunisation with two mV-I candidate vaccines, HIVA and HIVconsv. IL-10R blockade resulted in a trend towards increased IFN-y production by CD8+ T cells in response to the dominant H (Env) and P (Pol) epitopes of HIV A, and a significant increase in IFN-y ELISPOT responses to the subdominant Gl (Gag) epitope of HIV consv in vitro. Collectively, these data suggest that IL-10 producing cell populations may play critical but different roles in chronic infection and vaccination. Further research into how the timing of IL-10 responses affects disease outcome may allow IL-IO blockade to be explored as a therapeutic strategy in humans
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OBAFEMI, TOLULOPE FESAYO. "THE EFFECTS OF INTERLEUKIN 6 AND INTERLEUKIN 10 ON FRAILTY IN C57BL/6 MICE". Thesis, The University of Arizona, 2016. http://hdl.handle.net/10150/613394.
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Studies have shown that pro-inflammatory IL-6 and anti-inflammatory IL-10 interleukins may correlate to frailty and aging. This frailty can be defined in the context of clinical symptoms which include sarcopenia and osteoporosis, decreased activity level; or in the context of increased susceptibility to adverse health outcomes from a deficient immune system. In this experiment we tested a cohort of conditionally regulated IL-6 and IL-10 mice with controls (IL-6tg+.rtTA(r/r) (n=8), IL-10(-/-). IL-10tg+ rtTA(r/r) (n=10) and rtTA(r/r) (n=5)) under frailty assessments and immunological cell analysis. We were unable to successfully induce expression in the conditionally regulated mice. Subsequently, there was no difference in the frailty scores, weight, or temperature fluctuation between all three genotypes. As a preliminary study, there arose essential learning points of improvement that can be applied to future experiments concerning frailty in transgenic mice.
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Unterberger, Claudia. "Molekulare Mechanismen der Induktion von Interleukin-10 durch Glukokortikoide". Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-74135.
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Karimi, Sepideh. "Expression of interleukin-10 in vitro and in vivo". Thesis, University of Ottawa (Canada), 1994. http://hdl.handle.net/10393/6527.
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Classification of cytokines into T helper type 1 (Th1) and T helper type 2 (Th2) has helped in the elucidation of the mechanisms of resistance or susceptibility to infections. HIV infection causes CD4$\sp+$ T cell dysfunction and depletion by indirect mechanisms; for example: inhibition of immunoregulatory cytokines. Interleukin (IL-10), the subject of this study, is secreted mostly by CD4$\sp+$ human Th2-like, but also by Th0,Th1-like, and by a proportion of CD8$\sp+$ T cell clones. HIV sero-positive patients exhibit depressed cell mediated immune responses, B cell hyperplasia, and hypergammaglobulinemia which may result from downregulation of Th1 and upregulation of Th2 class responses respectively. In this study, the expression of interferon$\gamma$ (IFN$\gamma$) and IL-10 which mediate Th1 and Th2 responses respectively, in unstimulated peripheral blood lymphocytes (PBLs) from HIV$\sp+$ patients were investigated. IL-10 expression as observed by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis was significantly upregulated in patients with less than 400 CD4$\sp+$ T cells in comparison with HIV$\sp+$ patients with more than 400 CD4$\sp+$ T cells and normal controls. A semi-quantitative RT-PCR analysis of unstimulated PBLs further demonstrated IL-10 upregulation was inversely associated with IFN$\gamma$ downregulation in the same individuals. Similar results were observed as determined by measuring IL-10 and IFN$\gamma$ production in the supernatants of unstimulated PBLs by employing enzyme immunoassay techniques. These results suggest that HIV infected individuals express predominately Th2 type cytokines in their PBLs.
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Chang, Wen-Lan William. "Genetic and functional dissection of rhesus cytomegalovirus interleukin-10 /". Connect to Digital dissertations. Restricted to UC campuses. Access is free to UC campus dissertations, 2002. http://uclibs.org/PID/11984.
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Azbil, Tatiana. "Nachweis von Candida-Spezies und Bestimmung der Zytokine Interleukin-1 beta, Interleukin-1ra, Interleukin-4, Interleukin-6, Interleukin-8, Interleukin-10 und Interleukin-12 im Vaginalsekret und im Serum bei Schwangeren in Relation zum Gestationsalter". Diss., lmu, 2006. http://nbn-resolving.de/urn:nbn:de:bvb:19-57576.
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Cavendish, Victoria Jane. "The regulation of tumour necrosis factor-alpha and interleukin-10 by interleukin-13 in monocytic cells". Thesis, University of Bristol, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392976.
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Dokka, Sujatha. "IL-10 gene therapy for the treatment of pulmonary inflammation". Morgantown, W. Va. : [West Virginia University Libraries], 2000. http://etd.wvu.edu/templates/showETD.cfm?recnum=1421.
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Thesis (Ph. D.)--West Virginia University, 2000.Title from document title page. Document formatted into pages; contains ix, 132 p. : ill. (some col.) Vita. Includes abstract. Includes bibliographical references.
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Kampshoff, Jörg. "Die Wirkung der Interleukine 4, 10 und 13 auf die Koinkubation von Endothelzellen und mononukleären Zellen, gemessen an der Freisetzung von PDGF, Interleukin-1-[beta] [Interleukin-1-beta] und Interleukin-6". [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972057684.
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VanDeusen, Jeffrey Bryan. "A role for stat-1 in regulating interleukin 10 production following LPS challenge". Connect to this title online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1084860074.
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Thesis (Ph. D.)--Ohio State University, 2005.Title from first page of PDF file. Document formatted into pages; contains ix, 64 p.; also includes graphics (some col.). Includes bibliographical references (p. 54-64). Available online via OhioLINK's ETD Center.
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Dockstader, Kristy. "Role of interleukin-10 in lung repair during influenza infection". Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/59050.
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The mammalian lung is intricately designed for effective gas exchange. However, infections such as influenza can damage the lung tissue and can cause a critical decrease in lung performance.
Influenza is a single stranded RNA virus from the Orthomyxoviridae family. Seasonal influenza outbreaks cause up to 600 deaths in Canada each year, with increased death tolls during years with pandemic strains. Influenza A virus primarily infects the epithelial cells of the respiratory system and leads to acute respiratory infections.
Tissue destruction occurs both as a result of viral-mediated apoptotic pathways, and as a consequence of the cytolytic immune response that is essential to bring the infection under control. The immune system attempts to minimize damage by producing key anti-inflammatory molecules, of which Interleukin-10 (IL-10) is a particularly potent example.
IL-10 is a pleotropic cytokine that not only functions as an anti-inflammatory cytokine, but has been shown to have a role in immune stimulation, increase cytoskeletal repair and aid in the recovery of epithelial integrity. We hypothesized that IL-10 may have an effect on the remodeling and repair of lung epithelium during and after influenza A virus infection. We determined that IL-10 is up-regulated in response to infection. The timing of increased IL-10 also coincided with the height of damage, inflammation and onset of repair during an influenza infection. We used a human bronchial epithelial cell line (16HBE) to develop a model to assess if IL-10 had a direct effect on epithelial repair. Preliminary data suggested that IL-10 may inhibit epithelial cell proliferation, but further research is required.
Our data suggest that IL-10 does not appear to have a role in direct epithelial proliferation but could still have a role in repair. A better understanding of the signals involved in epithelial cell repair could lead to the development of novel therapies that will minimize/mitigate lung damage caused by influenza, as well as other lung diseases.Science, Faculty of
Microbiology and Immunology, Department of
Graduate
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Le, Moine Olivier. "Interleukin-10 in liver ischaemia-reperfusion injury and alcoholic cirrhosis". Doctoral thesis, Universite Libre de Bruxelles, 1996. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/212296.
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Williams, Lynn Michelle. "A comparison of interleukin-10 and lipopolysaccharide signalling in monocytes". Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264968.
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Chong, Wai-po, i 莊偉波. "Association of interleukin 10 promoter polymorphisms with systemic lupus erythematosus". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B29295981.
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Thompson, Kerry C. "The expression and function of interleukin-10 in liver injury". Thesis, University of Southampton, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285873.
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Madan, Rajat. "Novel insights into the in vivo biology of Interleukin-10". University of Cincinnati / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1242133534.
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Wendland, Sylke [Verfasser]. "Interleukin-6-, Interleukin-10- und TNF-alpha-Plasmaspiegel bei Patienten mit transplantations-assoziierter lymphoproliferativer Erkrankung / Sylke Wendland". Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2013. http://d-nb.info/1035406365/34.
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Asselineau, Delphine. "Le polymorphisme du promoteur de l'interleukine-10 et son rôle éventuel dans la maladie d'Alzheimer". Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066089.
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La maladie d'Alzheimer (MA) est une maladie neurodégénérative irréversible et progressive entraînant des troubles cognitifs et comportementaux. L'inflammation est caractéristique de la MA. L'interleukine-10 (IL-10), une cytokine anti-inflammatoire a été associée à un risque plus faible de développer la MA. Cependant le lien entre l'IL-10 et la progression de la MA n'a jamais été étudié. Le but de cette thèse a été d'étudier le rôle de l'IL-10 dans le développement ainsi que dans la progression de la MA. Pour mener à bien cette étude, 31 sujets atteints par la MA et 20 sujets contrôles cognitivement intacts ont été recrutés. En fonction de la vitesse de diminution du test de Mini-Mental State Examination et de l’évolution des troubles cognitifs sur deux ans, les patients souffrant de la MA ont été divisés en deux sous-groupes: les patients avec une progression lente (MA lent) et ceux avec une progression rapide (MA rapide). Les analyses se sont portées sur la concentration d’IL-10 en périphérie (plasma, production par les cellules mononuclées du sang périphérique (PBMCs) après stimulation par les peptides Aβ) ainsi que le polymorphisme de son promoteur en position -592, -819 et -1082. En complément, d’autres cytokines impliquées dans l’inflammation ont été étudiées : l’IL-6 (sa concentration plasmatique, sa production par les PBMCs à la suite d’une stimulation par les peptides Aβ et son polymorphisme en position -174) et les polymorphismes du TGF-β1 (-10 et - 25), de l’IFN-γ (-874) et du TNF-α (-308) ainsi que le gène de l'apolipoprotéine E (ApoE). Une étude de la longueur des télomères, liée à l’inflammation, a été aussi réalisée. Les résultats ont montré une association entre le génotype AA et l’allèle A du polymorphisme de l’IFN-γ en position -874 avec la progression rapide de la MA. Une augmentation statistiquement significative de la production d'IL-10 après stimulation par les peptides Aβ a été montrée chez les patients atteints avec une progression lente (MA lent). Une longueur significativement plus courte des télomères a été aussi associée aux patients MA lent. L’ensemble de ces travaux suggère qu’un profil de forte production de l’IL-10 ainsi qu’un profil génétique d’IFN-γ (TT -874) pourrait ralentir la progression de la MA. Il est aussi apparu que la longueur des télomères pourrait être un marqueur du déficit cognitif. Il est clair que ces résultats préliminaires ont besoin d’être confirmés par une étude de plus grande envergure, avec un nombre de patients plus élevéAlzheimer’s disease (AD) is an irreversible and progressive neurodegenerative disorder leading to cognitive and behavioral impairment. Inflammation is hallmark of AD although the exact mechanisms involved and the roles of the different inflammatory components are far less clear. Interleukin-10 (IL-10) is a key anti-inflammatory cytokine and IL-10 -1082 A > G polymorphism has been associated with a lower risk of developing AD although the link between IL-10 and the AD progression have never been studied. The aim of this study is to study the role of IL-10 in the risk of developing AD and its role in AD progression. In order to complete successfully this study, 31 AD patients and 20 cognitively intact controls were recruited. Depending of the rate of decrease of mini-mental state test examination (MMSE) and evolution of cognitive disorders, AD patients were divided in two subgroups: patients with slow progression (AD slow) and those with fast progression (AD fast). Analysis were focused on periphery concentration of IL-10 (plasma and and its production by peripheral blood mononuclear cells (PBMCs) after Aβ peptides stimulation) as well as its promoter polymorphism in position -592, -819 and -1082. In addition, other cytokines involved in inflammation were studied: IL-6 (its plasma concentration, its production by PBMCs following stimulation with Aβ peptides and its polymorphism at position -174) and polymorphisms of TGF-β1 (-10 to - 25), IFN-γ (-874) and TNF-α (-308) as well as the gene polymorphisms of Apolipoprotein E (ApoE). A study of telomere length, link to inflammation, was also performed. Results showed IFNγ -874AA genotype and -874A allele was associated with AD fast progression. A statistically significant increase of IL-10 production by PBMCs stimulated with Aβ peptides was shown in AD slow patients. A significantly shorter telomere length was also associated with AD slow patients. All of this work suggests that a profile with high IL-10 production and high IFN-γ (-874 TT) genotype could confer a slower AD progression. It was also found that telomere length may be a marker of cognitive impairment. It is clear that these preliminary results need to be confirmed in a larger study with a larger number of patients
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Frisch, Kristina. "Klonierung von IL-10 und IL-10-Homologen und Funktionsanalyse in einem Mausmodell der polymikrobiellen Sepsis". [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=973392185.
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Ramos, Rodrigo Nalio. "The immunosuppressive microenvironment in cancer : local and systemic effects on patients' monocytes". Thesis, Lyon 1, 2015. http://www.theses.fr/2015LYO10270.
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Chez les patients atteints de cancer, les cellules néoplasiques échappent au contrôle du système immunitaire en raison de leur faible immunogénicité et d'une capacité exacerbée à moduler le micro-environnement. Nous décrivons ici les effets de ce micro-environnement tumoral sur la différenciation locale et systémique des monocytes et l'impact de la présence de Macrophages-Associés aux Tumeurs (TAM) CD163+ sur la survie des patientes atteintes de cancer du sein. Par une analyse de cytométrie en flux, nous décrivons un composition hétérogène des sous-types de TAM CD163low et CD163high, où nous avons observé l'association entre une fréquence élevée de TAM CD163high et une faible infiltration des lymphocytes T CD3+. Par immunohistochimie sur une analyse rétrospective (±12 ans), nous avons démontré une forte corrélation entre la fréquence élevée de TAM CD163+ et un risque accru de progression pour les patientes (log-rank *p<0.05, n=238). In vitro, les monocytes CD14+ conditionnés par le micro-environnement tumoral présentent une différenciation biaisée en faveur des MΦ CD163highCD86lowIL-10high, que non seulement ne stimulent pas la prolifération des lymphocytes T CD4+ naïfs, mais inhibent fortement l'expansion et la production d'IFN-γ et de TNF-α par les lymphocytes T CD4+ préalablement activé. Cette différenciation de MΦ en M2-like (CD163highIL-10high) est associée à des quantités élevées de TGF-β, M-CSF et VEGF dans le micro-environnement tumoral. Par ailleurs, les monocytes circulants des patientes atteintes de cancer du sein présentent un profil cytokinique immunosuppresseur et sont biaisés vers une différenciation en MΦ et Mo-DCs qui présentant des capacités suppressivesIn cancer patients, the neoplastic cells escape from the immune control because of their low immunogenicity and their exacerbated capacity to modulate the microenvironment. Here we describe the local and systemic effects of the tumor microenvironment on monocyte differentiation and the impact of the presence of Tmor Associated Macrophages (TAM) CD163+ on the survival of breast cancer patients. By flow cytometry analysis, we describe a heterogeneous composition of CD163low and CD163high TAM subtypes, where we observed the association between high frequency of CD163high TAM infiltration and low CD3+ T lymphocytes presence. By immunohistochemistry on a retrospective analysis (±12 years), we have shown a strong correlation between high frequency CD163+ TAM and an increased risk of progression for patients (log-rank *p<0.05, n= 238). In vitro, CD14+ monocytes conditioned by tumor microenvironment exhibit a biased differentiation towards a CD163highCD86lowIL-10high macrophages (MΦ) phenotype, that not only failed to stimulate the proliferation of naive CD4+ T cells, but strongly inhibited the expansion and the production of IFN-γ and TNF-α by activated-CD4+ T cells. This differentiation into M2-like MΦ (CD163highIL-10high) is associated with high levels of TGF-β, M-CSF and VEGF found in the tumor microenvironment. Furthermore, circulating monocytes of breast cancer patients produced an immunosuppressive cytokine profile and are biased towards the differentiation into MΦ and Mo-DCs that show suppressive capacities
O desenvolvimento do câncer é normalmente associado a desvios no sistema imune, principalmente devido a sua falha em perceber, reconhecer e eliminar células neoplásicas de maneira eficiente. Nesse contexto, duas Células Apresentadoras de Antígenos (APCs), Células Dendríticas (DCs) e Macrófagos (MΦ), têm um papel crucial na identificação de alterações nos tecidos e na estimulação da imunidade adaptativa antitumoral. No entanto, fatores derivados de tumores modulam essas APCs, impedindo a iniciação das respostas imunes e culminando no estabelecimento do câncer. Investigamos aqui como o microambiente tumoral poderia modular a diferenciação de monócitos em APCs in vitro e de modo sistêmico. Nossos dados revelaram que em cânceres de mama e ovário, Macrófagos-Associados a Tumores (TAMs) são a subpopulação mais frequente em leucócitos CD45+MHCII+, e são encontrados em uma frequência variável de TAMs CD163low ou TAMs CD163high. O último, (TAMs CD163high) expressaram maiores níveis de PD-L1 e elevada produção de IL-10 sob a ativação de LPS. Além disso, a análise retrospectiva por imunohistoquímica revelou uma forte correlação entre a presença de TAMs CD163+ e uma baixa taxa de sobrevida em pacientes com câncer de mama. Ainda, a alta frequência de TAMs CD163high foi correlacionada com um baixo infiltrado de células T CD3+. Monócitos saudáveis condicionados por sobrenadantes de tumores de mama tiveram sua diferenciação in vitro direcionada para um fenótipo CD163highIL-10high, células capazes de suprimir a expansão de células T naive CD4+ e a produção de IFN- γ e TNF-α via IL-10. Esse fenótipo adquirido por monócitos condicionados foi associado à presença de altos níveis de CCL22, M-CSF, TGF-β1, TGF-β3, e VEGF no microambiente tumoral. Interessantemente, avaliando os efeitos sistêmicos dos tumores, monócitos circulantes de pacientes com câncer de mama falharam em diferenciar-se em M1- MΦ na presença de GM-CSF/IFN-γ e mantiveram um fenótipo alterado CD163+/-IL-10+TNF-α+
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Schwarz, Annika. "Einfluss von Interleukin-10 auf die Differenzierung von Monozyten zu Dendritischen Zellen". Doctoral thesis, Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-148424.
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Interleukin-10 ist ein Paradebeispiel eines immunhemmenden Zytokins. Es konnte nachgewiesen werden, dass eine Reihe von Tumoren Interleukin-10 produziert, um einer Antitumor-Immunantwort zu entgehen. Viele Studien haben sich mit dem Einfluss von Interleukin-10 auf die antigenpräsentierenden Fähigkeiten der Dendritischen Zellen beschäftigt. Es gibt eindeutige Hinweise, dass der Effekt von tumorproduziertem Interleukin-10 nicht nur in einer hemmenden Wirkung auf die Ausreifung Dendritischer Zellen besteht, sondern dass Interleukin-10 zu einer Reduktion der Anzahl an Dendritischen Zellen führen kann. Ziel dieser Arbeit ist es daher, den Mechanismus für eine solche depletierende Wirkung auf die Dendritischen Zellen zu analysieren. Hierzu wurden die Effekte von Interleukin-10 auf die frühe Differenzierung von Dendritischen Zellen aus Monozyten untersucht.
Die Zugabe von Interleukin-10 zu einem Differenzierungscocktail aus Interleukin-4 und Granulozyten/Makrophagen-Kolonie-stimulierendem-Faktor führt zu einer nachhaltigen Hemmung des Differenzierungsprozesses von Monozyten zu Dendritischen Zellen. Bereits 48h nach Beginn der Zellkultur konnte mit Hilfe von cDNA-Microarray-Analysen gezeigt werden, dass Interleukin-10 nicht nur einen Differenzierungs-hemmenden Effekt ausübt, sondern auch die Entstehung aberranter Zellphänotypen bewirkt. In weiteren Experimenten konnte gezeigt werden, dass die Effekte des Interleukin-10 in der frühen Differenzierungsphase weitgehend irreversibel sind. Zusammenfassend können die Ergebnisse zur Erklärung beitragen, wie es bei Patienten mit Tumoren unter dem Einfluss von Interleukin-10 zu einer Reduktion der absoluten Zahl Dendritischer Zellen kommen kann.
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Wang, Allen Ping-Lun. "The effect of hypoxia on the production of interleukin-10 (IL-10) in human mononuclear cells". Thesis, University of Leicester, 2010. http://hdl.handle.net/2381/10228.
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Macrophages play an important role in both innate and adaptive immunity by engulfing intruding pathogens and damaged or infected cells, antigen presentation, and by secretion of immune mediators. Interleukin 10 (IL-10) is a potent anti-inflammatory cytokine mainly produced by macrophages in response to cell activation, which serves to suppress immune reactions and inflammation. Hypoxia refers to oxygen deprivation. It is a common condition found in pathological tissues. The relationship between hypoxia and the production of IL-10 by macrophage is not yet thoroughly understood. In previous unpublished work by Staples and Burke et. al., it was found that both basal and LPS-induced IL-10 mRNA and protein are reduced in hypoxia. In the present study, it was shown that the transcription factor Hypoxia Inducible Factor 1 (HIF-1) appears to be involved in this reduction of IL-10 production in hypoxia. Although the regulatory elements on the IL-10 promoter responsible for this blockage effect were not definitively identified, our results indicated that the activity of a -4kb IL-10 luciferase reporter adenovirus was significantly reduced in cells treated with the HIF-1 inducing agents, cobalt chloride and desferrioxamine. The activity of a -195bp IL-10 luciferase reporter adenovirus was also decreased in the HIF-1inducing agent treated samples. These data imply that either by indirect interaction or physically binding to the IL-10 promoter or gene, HIF-1 does play a role in blocking IL-10 expression in hypoxia. Sequence and transcription factor analysis indicated the presence of a HIF-1 consensus sequence hypoxia responsive element (HRE) located in the -2,171bp to -2,187bp position on the IL-10 promoter. This result suggests that HIF-1 may affect IL-10 production, at least in part, by physically binding to its promoter. Lastly, we showed that the effect of hypoxia on IL-10 expression is observed with a range of different toll-like receptor ligands, and is not limited to induction by LPS.
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Aydın, Gönül Karaaslan Tamer. "Deneysel omurilik yaralanmasında İnterlökin-10'un İnterlökin 1-Beta ve İnterlökin-6 üzerine etkilerinin incelenmesi /". Isparta : SDÜ Tıp Fakültesi, 2007. http://tez.sdu.edu.tr/Tezler/TT00331.pdf.
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Frellstedt, Linda. "Induction and characterization of endotoxin tolerance in equine peripheral blood mononuclear cells in vitro". Thesis, Virginia Tech, 2010. http://hdl.handle.net/10919/44307.
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Endotoxemia is responsible for severe illness in horses. Individuals can become unresponsive to the endotoxin molecule after an initial exposure; this phenomenon has been called developing a state of â endotoxin toleranceâ (ET). ET has been induced in horses in vivo; however, cytokine expression associated with ET has not been investigated. The purpose of this study was to develop and validate a method for inducing ET in equine peripheral blood mononuclear cells (PBMCs) in vitro, and to describe the cytokine profile which is associated with the ET. Blood was collected from 6 healthy horses and PBMCs were isolated. ET was induced by culturing cells with three concentrations of endotoxin given to induce ET, and evaluated after a second dose of endotoxin given to challenge the cells. The relative mRNA expression of IL-10 and IL-12 was measured by use of quantitative PCR.
ET was induced in all cells (n=6) exposed to the 2-step endotoxin challenge. In PBMCs treated with 1.0 ng/ml of endotoxin followed by challenge with 10 ng/ml of endotoxin, the relative mRNA expression of IL-10 in tolerized cells was not different from positive control cells. In contrast, the relative mRNA expression of IL-12 in tolerized cells was decreased by 15-fold after the second endotoxin challenge compared with positive control cells.
This experiment demonstrated a reliable method for the ex vivo induction of ET in equine PBMCs. A marked suppression of IL-12 production is associated with ET. The production of IL-10 was not altered in ET in our model.
Master of Science
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Gehrcke, Jan-Philip. "Investigation of the interleukin-10-GAG interaction using molecular simulation methods". Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-163205.
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Glycosaminoglycans (GAGs) are linear polysaccharides, built of periodically occurring disaccharide units. GAGs are ubiquitous in the extracellular matrix (ECM), where they exhibit multifarious biological activities. This diversity arises from - among others - their ability to interact with and regulate a large number of proteins, such as cytokines, chemokines, and growth factors. As of the huge variety in their chemical configuration, GAGs are further sub-classified into different types (heparin, for instance, is one of these sub-classes). Hence, GAGs are a diverse class of molecules, which surely contributes to the broadness of their spectrum of biological functions. Through varying arrangements of sulfate groups and different types of saccharide units, individual GAG molecules can establish specific atomic contacts to proteins. One of the best-studied examples is antithrombin-heparin, whose biologically relevant interaction requires a specific pentasaccharide sequence. It is valid to assume, however, that various proteins are yet to be discovered whose biological functions are in some way affected by GAGs. In other cases, and this is true for the cytokine interleukin-10 (IL-10), there are already experimental indications for a biologically relevant protein-GAG interaction, but the details are still obscure and the fundamental molecular interaction mechanism has still not been clarified.
IL-10 has been shown to bind GAGs. So far, however, no structural detail about IL-10-GAG interaction is known. Function-wise, IL-10 is mainly considered to be immunosuppressive and therefore anti-inflammatory, but it in fact has the pleiotropic ability to influence the immune system in both directions, i.e. it constitutes a complex regulation system on its own. Therefore, the role of GAGs in this system is potentially substantial, but is yet to be clarified. In vitro experiments have yielded indications for GAGs being able to modulate IL-10\'s biological function, and obviously IL-10 and GAGs are simultaneously present in the ECM. This gives rise to the assumption that IL-10-GAG interaction is of biological significance, and that understanding the impact of GAGs on IL-10 biology is important - from the basic research point of view, but also for the development of therapies, potentially involving artificially designed ECMs.
A promising approach for obtaining knowledge about the nature of IL-10-GAG interaction is its investigation on the structural level, i.e. the identification and characterization of the molecular interaction mechanisms that govern the IL-10-GAG system. In this PhD project it was my goal to reveal structural and molecular details about IL-10-GAG interaction with theoretical and computational means, and with the help of experiments performed by collaborators in the framework of the Collaborative Research Centre DFG Transregio 67. For achieving this, I developed three methods for the in silico investigation of protein-GAG systems in general and subsequently applied them to the IL-10-GAG system. Parts of that work have been published in scientific journals, as outlined further below.
I proposed and validated a systematic approach for predicting GAG binding regions on a given protein, based on the numerical simulation and analysis of its Coulomb potential. One advantage of this method is its intrinsic ability to provide clues about the reliability of the resulting prediction. Application of this approach to IL-10 lead to the observation that its Coulomb attraction for GAGs is significantly weaker than in case of exemplary protein-GAG systems (such as FGF2-heparin). Still, a distinct IL-10-GAG binding region centered on the residues R102, R104, R106, R107 of the human IL-10 sequence was identified. This region can be assumed to play a major role in IL-10-GAG interaction, as described in chapter 3.
Molecular docking methods are used to generate binding mode predictions for a given receptor-ligand system. In chapter 4, I clarify the importance of data clustering as an essential step for post-processing docking results and present a clustering methodology optimized for GAG molecules. It allows for a reproducible analysis, enabling systematic comparisons among different docking studies. The approach has become standard procedure in our research group. It has been applied in a variety of studies, and served as an essential tool for studying IL-10-GAG interaction, as described in chapter 3.
Motivated by the shortcomings of classical docking approaches, especially with respect to protein-GAG systems, I worked on the development of a molecular dynamics-based docking method with less radical approximations than usually applied in classical docking. The goal was to make the computational model properly account for the special physical properties of GAGs, and to include the effects of receptor flexibility and solvation. The methodology was named Dynamic Molecular Docking (DMD) and published in the Journal of Chemical Information and Modeling-together with a validation study.
The subsequent application of DMD in a variety of studies required enormous amounts of computational resources. For tackling this challenge, I established a graphics processing unit-based high-performance computing environment in our research group and developed a software framework for reliably performing DMD studies on this hardware, as well as on other computing resources of the TU Dresden. The investigation of the IL-10-GAG system via DMD was focused on the IL-10-GAG binding region predicted earlier, and made heavy usage of the optimized clustering approach named above. An important result of this endeavor is that IL-10's amino acid residue R107 significantly stands out compared to all other residues and supposedly plays a particularly important role in IL-10-GAG recognition. The collaboration with the NMR laboratory of Prof. Daniel Huster at the Universität Leipzig was fruitful: I post-processed nuclear Overhauser effect data and obtained heparin structure models, which revealed that IL-10-heparin interaction has a measurable impact on the backbone structure of the heparin molecule. These results were published in Glycobiology. In chapter 8, I propose two different scenarios about how GAG-binding to IL-10 might affect its biological function, based on the findings made in this thesis project.
In conclusion, a set of methods has been developed, all of which are generically applicable for the investigation of protein-GAG systems. Regarding the IL-10-GAG system, valuable structural insights for increasing the understanding about its molecular mechanisms were derived. These observations pave the way towards unraveling GAG-mediated bioactivity of IL-10, which may then be specifically exploited, for instance in artificial ECMs for improved wound healing.
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Schardt, Victor [Verfasser], i Ernst Rainer [Akademischer Betreuer] Weissenbacher. "Vergleichende Untersuchungen zur Hefepilzbesiedelung von Mundhöhle und Vagina und Bestimmung von Interleukin-4, Interleukin-10 und Interleukin-12 / Victor Schardt. Betreuer: Ernst Rainer Weissenbacher". München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2013. http://d-nb.info/1032862645/34.
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Künze, Georg. "Untersuchungen zur Wechselwirkung von Interleukin-10 mit Glykosaminoglykanen mittels NMR-Spektroskopie". Doctoral thesis, Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-176115.
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Das Zytokin Interleukin-10 (IL-10) ist ein Schlüsselspieler in der Regulation des Immunsystems mit pro- und anti-inflammatorischen Funktionen. Es spielt eine wichtige Rolle bei der Terminierung und Unterdrückung einer Entzündungsantwort, die ansonsten zu einer bleibenden Schädigung des Gewebes führen kann. Eine Dysregulation von IL-10 ist mit verschiedenen Krankheitsbildern wie chronischen Entzündungen, Autoimmunerkrankungen und Krebs assoziiert. IL-10 wird von einem breiten Spektrum von Zelltypen, darunter hauptsächlich hämatopoetische Zellen, aber auch epitheliale und mesenchymale Zellen, gebildet und in den extrazellulären Raum freigesetzt, wo es mit Komponenten der extrazellulären Matrix in Kontakt kommt. Es ist bekannt, dass IL-10 an Glykosaminoglykane (GAGs) binden kann und dass diese Interaktion seine biologische Aktivität beeinflusst. GAGs sind eine Klasse linearer Polysaccharide der extrazellulären Matrix. Sie bestehen aus wiederholenden Disaccharideinheiten und haben einen hoch negativ geladenen Charakter, welcher durch einen hohen Grad an Sulfatierung in der Zuckerkette zustandekommt. Sie binden eine Vielzahl an Signalproteinen und regulieren deren biologische Funktionen, etwa indem sie Einfluss auf die Rezeptorbindung oder die räumliche Verteilung des Proteins im Gewebe nehmen. Die molekularen Mechanismen, wodurch GAGs die biologische Aktivität von IL-10 beeinflussen, sind bisher unbekannt. Insbesondere ist nichts über die strukturellen Grundlagen der Interaktion bekannt, die Voraussetzung für ihr funktionelles Verständnis sind. In dieser Arbeit wurden daher die Bindungseigenschaften von IL-10 und GAGs sowie der strukturelle Aufbau ihres molekularen Komplexes unter Verwendung von NMR-Spektroskopie in Lösung charakterisiert. Es wurde eine definierte GAG-Bindungsstelle in IL-10 identifiziert und die Bindungsepitope und Bindungsaffinitäten von GAGs bestimmt. Die Ergebnisse dieser Arbeit weisen auf eine wichtige Rolle, die GAGs in der Biologie von IL-10 spielen können, hin – etwa für seine Speicherung im Gewebe oder für die IL-10-Rezeptorbindung.
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Etling, Michele R. "THE AGING MUCOSAL IMMUNE SYSTEM IN THE INTERLEUKIN-10-DEFICIENT MOUSE". Case Western Reserve University School of Graduate Studies / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1184295867.
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Wong, Justine Karoline. "HIV-1 Tat-induced interleukin-10 from monocytes is subtype specific". Diss., [La Jolla] : University of California, San Diego, 2009. http://wwwlib.umi.com/cr/ucsd/fullcit?p1465088.
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Thesis (Ph. D.)--University of California, San Diego, 2009.Title from first page of PDF file (viewed June 22, 2009). Available via ProQuest Digital Dissertations. Includes bibliographical references (p. 27-35).
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Taubert, Christina Maria. "Molecular mechanisms underlying the regulation of interleukin-10 production in macrophages". Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/10034083/.
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Interleukin (IL)-10 is an immunosuppressive cytokine that plays a crucial role in preventing inflammatory and autoimmune pathology. The dysregulation of IL-10 during infection can lead to either an over-exuberant response damaging the host, or conversely ineffective pathogen clearance. Macrophages are important players in inflammatory responses and produce IL-10 in response to Toll-like receptor (TLR) ligation along with protective pro-inflammatory cytokines. The collective regulation of these cytokines is central to the generation of an effective but balanced immune response. We observed that type I IFN is one factor that leads to differential production of IL-10 and pro-inflammatory cytokines in TLR4 stimulated C57BL/6 and BALB/c macrophages. The effects of type I IFN on pro-inflammatory cytokine production were IL-10 dependent and independent. Hence, we further investigated how type I IFN regulates IL-10 production and showed that type I IFN acts as a transcriptional regulator of Il10 mRNA via activation of ERK1/2, and additionally stabilises Il10 mRNA transcripts in TLR4 stimulated macrophages. Using an assay for transposase-accessible chromatin with high throughput sequencing we further unravelled how type I IFN regulates Il10 transcription. We were able to demonstrate that type I IFN increases chromatin accessibility and augments the recruitment of the transcription factors ATF3 and JUNB to the Il10 locus in macrophages upon LPS stimulation. These findings highlight key pathways responsible for the type I IFN-dependent regulation of IL-10, and may provide valuable information for the development of immunomodulatory treatments of inflammatory diseases.
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Blalock, Emily L. "Roles of TH2 and TH17 CD4+ T-Helper Cell Cytokines in the Pathogenesis of Experiemental Cytomegalovirus Retinitis". Digital Archive @ GSU, 2012. http://digitalarchive.gsu.edu/biology_diss/122.
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Human cytomegalovirus (HCMV) is a betaherpesvirus that infects up to 80% of the population worldwide, and establishes latency in monocytes and bone marrow cells. Reactivated HCMV can become an opportunistic pathogen in individuals who are immunocompromised, such as those with acquired immunodeficiency syndrome (AIDS). HCMV infection of AIDS patients causes a sight-threatening retinitis that leads to vision loss and blindness in up to 46% of this population without antiretroviral treatment. Because untreated HIV-infected individuals exhibit the loss of cell-mediated immunity and alterations in CD4+ T-helper (Th) cell cytokines, including elevation of interleukin-4 (IL-4), IL-10, and IL-17, we sought to test the hypothesis that these cytokines play key roles in governing the susceptibility to AIDS-related HCMV retinitis. This hypothesis was tested utilizing a clinically relevant mouse model of experimental murine cytomegalovirus (MCMV) retinitis that occurs in C57BL/6 mice immunosuppressed by mouse retroviruses (MAIDS). Studies revealed that MAIDS progression was associated with increased levels of IL-4 and IL-10, cytokines whose production has been associated with diminished CD8+ T-cell-mediated immunity during HIV infection. However, MCMV–infected eyes of retinitis-susceptible IL-4-/- or IL-10-/- MAIDS mice exhibited frequency and severity of retinitis and viral titers equivalent to MCMV-infected eyes of wild-type MAIDS animals. These studies indicated that neither IL-4 nor IL-10 alone play key roles in increased susceptibility to MCMV retinitis. In comparison, IL-17, an inflammatory cytokine associated with the ocular autoimmune disease uveitis, was systemically increased during the progression of MAIDS, but MCMV-infected eyes of retinitis-susceptible MAIDS mice exhibited a significant reduction in IL-17. These findings suggested that IL-17 plays no direct role in the pathogenesis of experimental MCMV retinitis. However, these results also suggested the remarkable possibility that MCMV downregulates IL-17 production, a hypothesis supported by the observation that systemic MCMV infection of healthy and MAIDS mice resulted in the downregulation of IL-17. Mechanistic studies revealed that knockdown of IL-10 resulted in a partial recovery IL-17 levels during MCMV infection. We conclude that MCMV-induced IL-17 downregulation occurs via the stimulation of IL-10 and the suppressor of cytokine signaling (SOCS)-3. Taken together, our results add new information to the immunobiology of HCMV and to our basic understanding of the pathogenesis of AIDS-related HCMV retinitis.
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Costa, Ana Carolina Vieira da. "Avaliação da produção de interleucina 6, fator de necrose tumoral e interleucina 10 em hemoculturas de pacientes com Leishmaniose Cutânea localizada". Universidade Federal de Goiás, 2017. http://repositorio.bc.ufg.br/tede/handle/tede/7243.
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Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG
American Tegumentary Leishmaniasis (ATL) is caused by protozoa of the genus Leishmania. The parasite is hosted by macrophages in cutaneous or mucosal lesions. Monocytes are precursors of macrophages, but there is little information about monocyte activation during ATL. The present study aimed to evaluate cytokine profile of monocytes from patients with localized cutaneous leishmaniasis (LCL) in whole blood cultures stimulated with toll-like receptor (TLRs) and NOD2 receptor agonists. Peripheral blood from patients with active lesions and no treatment, and from healthy blood donors paired by sex and age, was diluted into culture medium and incubated with lipopolysaccharide (LPS), TLR4 agonist; lipopeptide Pam3Cys (Pam), TLR2 agonist; muramyldipeptide (MDP), NOD2 agonist or Leishmania (V.) braziliensis antigen (Ag). After incubation, supernatants were collected to measure IL-6 and TNF (6 h) and IL-10 (24 h) by ELISA. There was production of IL-6, TNF and IL-10 in cultures from patients and controls after stimulation with all agonists and Ag (p < 0.05, medium vs stimulus, n = 29). No differences were detected between concentrations of TNF and IL-10, but IL-6 was higher produced in non-stimulated cultures from patients than controls (p < 0.05, n = 29) or when the stimulus was MDP (p < 0.05, n = 19). The combination Pam/MDP increased the production of IL-6, TNF and IL-10 in cultures from patients and controls when compared with each stimulus isolated (p < 0.05, n = 13 - 14); similarly, Ag and MDP together induced higher concentrations of IL-6, TNF and IL-10 (IL-6 and IL-10, especially in cultures from patients) in comparison with each stimulus (p < 0.05, n = 11 - 14). There was no correlation between the number, size or time of lesions and levels of IL-6, TNF or IL-10. Patients with more than one cycle of treatment to obtain clinical cure showed higher levels of MDP-induced IL-6 than those cured with one cycle of treatment (p < 0.05, n = 17 cured with one cycle vs 8 cured with more than one cycle). Data suggest that LCL patient monocytes can be activated via TLR2, TLR4 or NOD2 to produce pro-inflammatory (IL-6, TNF) and anti-inflammatory (IL-10) cytokines and IL-6 can be associated with tissue lesion and delay of lesion healing indicating an immunopathogenic role in LCL.
A Leishmaniose Tegumentar Americana (LTA) é causada por protozoários do gênero Leishmania, que acomete a pele e/ou mucosas. Os monócitos são precursores de macrófagos, células hospedeiras do parasito, e pouco se sabe sobre seu nível de ativação durante a LTA. O presente estudo teve como objetivo avaliar o perfil de resposta de citocinas produzidas por monócitos de pacientes com leishmaniose cutânea localizada (LCL) em hemoculturas, após ativação com agonistas de receptores similares a toll (TLRs) e de receptor NOD2. O sangue periférico de pacientes com LCL, com lesões ativas e sem tratamento, e de indivíduos controles, pareados por sexo e idade, foi diluído em meio de cultura e incubado com lipopolissacarídeo (LPS), agonista de TLR4; lipopeptídeo Pam3Cys (Pam), agonista de TLR2; muramildipeptídeo (MDP), agonista de NOD2 ou antígenos de Leishmania (V.) braziliensis (Ag). Após incubação, os sobrenadantes foram colhidos para dosagem de IL6 e TNF (6 h) e IL-10 (24 h), por ELISA. Nas hemoculturas dos pacientes e dos controles, houve produção de IL-6, TNF e IL-10, após incubação com todos os estímulos (p < 0,05, Meio vs estímulos, n = 29). Ao comparar pacientes e controles, não houve diferença quanto à produção de TNF e IL-10, mas a produção de IL-6 foi maior nas hemoculturas não estimuladas dos pacientes (p < 0,05, n = 29) e na presença do MDP (p < 0,05, n = 19). A combinação Pam/MDP aumentou a produção de IL-6, TNF e IL-10 nas hemoculturas dos pacientes e controles, em relação a cada estímulo sozinho (p < 0,05, n = 13 - 14); de maneira similar, Ag e MDP juntos aumentaram a concentração de IL-6, TNF e IL-10 (IL-6 e IL-10, especialmente nas hemoculturas dos pacientes) (p < 0,05, n = 11 - 14). Não houve correlação significante entre o número, o tamanho e o tempo das lesões dos pacientes com LCL e as concentrações de IL-6, TNF e IL-10 nas hemoculturas dos mesmos. Quando comparados os pacientes clinicamente curados após um ciclo de medicamento e aqueles clinicamente curados após mais de um ciclo de medicamento em relação às concentrações de TNF e IL-10 não foram detectadas diferenças significantes entre os grupos, porém, em relação à produção de IL-6, foi observado que esta foi mais elevada nos pacientes curados com mais de um ciclo de medicamento, após o estímulo MDP (p < 0,05, n = 17 curados com 1 ciclo vs 8 xv curados com mais de 1 ciclo). Os dados sugerem que os monócitos de pacientes com LCL podem ser ativados via TLR2, TLR4 e NOD2, induzindo a produção de citocinas pró-inflamatórias (IL-6, TNF) e anti-inflamatória (IL-10) e a IL-6 pode estar associada ao dano tecidual e a demora na cura dos pacientes, possuindo um papel imunopatogênico na LCL humana.
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Vendruscolo, Cynthia do Prado. "Avaliação dos efeitos inflamatório e oxidante do ozônio medicinal em articulações sinoviais de equinos hígidos". Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/10/10136/tde-25052017-133250/.
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A ozonioterapia consiste na aplicação de ozônio medicinal, uma mistura de ozônio e oxigênio, que através das espécies reativas de oxigênio e produtos de lipoperoxidação exercem diversos efeitos no organismo como, melhora da oxigenação e metabolismo dos tecidos, angiogênese, aumento dos mecanismos antioxidantes, melhora do sistema imune, efeito anti-inflamatório, entre outros. Esta modalidade terapêutica já é amplamente estudada na medicina humana e vem sendo aplicada na medicina esportiva equina no tratamento de osteoartrite, porém sem estudos expressivos que comprovem sua segurança e eficácia. O objetivo do presente estudo é analisar os efeitos inflamatório e oxidante do ozônio medicinal em articulações sinoviais de equinos hígidos. Para tanto foram utilizadas 24 articulações tibiotársicas distribuídas aleatoriamente em três grupos. Nos grupos tratados foram realizadas três aplicações semanais de 15 ml de ozônio medicinal na concentração de 20 (GA) e 40 µg/ml (GB), no total de 10 aplicações. Já no grupo controle, as articulações receberam três aplicações semanais de 15 ml de O2 (GC), também no total de dez aplicações. Foram realizados exames físico, de claudicação e ultrassonográfico, bem como análise do líquido sinovial, incluindo contagem total de células nucleadas e quantificação de proteína total, prostaglandina E2, Substância P, interleucina-1, interleucina-6, interleucina 10, fator de necrose tumoral-α, ácido hialurônico (concentração e peso molecular) e condroitim sulfato. Para avaliação antioxidante no líquido sinovial foi determinada a atividade da superóxido desmutase e o burst oxidativo. Houve aumento da temperatura em GA e GB, os animais de GB apresentaram maior claudicação comparado aos demais grupos e observou-se aumento em todos os grupos dos escores ultrassonográficos. Na análise do líquido sinovial observou-se aumento nas contagens celulares de GA e GB, acompanhado de polimorfonucleares em GB, aumento da concentração de proteína no GA e GB, da atividade da superóxido desmutase e do índice de ativação em GA e diminuição da concentração de ácido hialurônico em todos os grupos e condroitim sulfato em GB e GC. Não houve diferença nas concentrações de PGE2, substância P, IL-1, IL-6, IL-10 e TNF-α. A aplicação consecutiva do ozônio medicinal intra-articular provocou alterações ultrassonográficas e no exame de claudicação, mais perceptível na dose de 40 ug/mL. Estas alterações estão mais relacionadas à distensão articular causada pela infusão de gases do que aos efeitos inflamatórios provindos do O3, uma vez que as análises de líquido sinovial não mostraram relevante inflamação. Conclui-se que a aplicação intra-articular de ozônio medicinal em equinos é segura em ambas as doses, e que experimentos devem ser realizados utilizando-se animais com diferentes doenças articulares, para que os benefícios da ozonioterapia sejam evidenciados e compreendidos.Ozone therapy consists of the application of medicinal ozone, a mixture of ozone and oxygen, which through reactive oxygen species and products of lipoperoxidation exert various effects on the body, such as improvement of tissue oxygenation and metabolism, angiogenesis, increase of antioxidant mechanisms, improvement of the immune system, anti-inflammatory effect, among others. This therapeutic modality is already widely studied in human medicine and has been applied in equine sports medicine in the treatment of osteoarthritis, but without expressive studies that prove its safety and efficacy. The objective of the present study is to analyze the inflammatory and oxidizing effects of medicinal ozone on synovial joints of healthy horses. Twenty-four tibiotarsic joints were randomly distributed in three groups. In the treated groups three weekly applications of 15 ml of medicinal ozone in the concentration of 20 (GA) and 40µg / ml (GB) were carried out for a total of 10 applications. Already in the control group, the joints received three weekly applications of 15 ml of O2 (GC), also in the total of 10 applications. Physical, lameness and ultrasound examinations were performed, as well as synovial fluid analysis, including total nucleated cell count and quantification of total protein, prostaglandin E2, Substance P, interleukin-1, interleukin-6, interleukin-10, tumor necrosis factor-α, hyaluronic acid (concentration and molecular weight) and chondroitin sulfate. For the antioxidant evaluation in the synovial fluid, the activity of the superoxide dismutase and the oxidative burst was determined. There was an increase in temperature in GA and GB, GB animals presented greater lameness compared to the other groups and an increase was observed in all groups of ultrasound scores. In the synovial fluid analysis, GA and GB cell counts were observed, followed by polymorphonuclear cells in GB, increased protein concentration in GA and GB, superoxide desmutase activity and activation index in GA, and decrease in concentration of Hyaluronic acid in all groups and chondrocyte sulfate in GB and CG. There was no difference in the concentrations of PGE2, substance P, IL-1, IL-6, IL-10 and TNF-α. The consecutive application of intra-articular medicinal ozone caused ultrasonography changes and lameness, more noticeable at 40 ug / mL. These changes related more to joint distension caused by gas infusion than to inflammatory effects from O3, since synovial fluid analyzes did not show relevant inflammation. It is concluded that the intra-articular application of medical ozone in horses is safe in both doses, and that experiments must be performed using animals with different joint diseases, so that the benefits of ozonotherapy are evidenced and understood.
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Ruiz-Gómez, Gloria, John C. Hawkins, Jenny Philipp, Georg Künze, Robert Wodtke, Reik Löser, Karim Fahmy i M. Teresa Pisabarro. "Rational Structure-Based Rescaffolding Approach to De Novo Design of Interleukin 10 (IL-10) Receptor-1 Mimetics". Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-215877.
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Tackling protein interfaces with small molecules capable of modulating protein-protein interactions remains a challenge in structure-based ligand design. Particularly arduous are cases in which the epitopes involved in molecular recognition have a non-structured and discontinuous nature. Here, the basic strategy of translating continuous binding epitopes into mimetic scaffolds cannot be applied, and other innovative approaches are therefore required. We present a structure-based rational approach involving the use of a regular expression syntax inspired in the well established PROSITE to define minimal descriptors of geometric and functional constraints signifying relevant functionalities for recognition in protein interfaces of non-continuous and unstructured nature. These descriptors feed a search engine that explores the currently available three-dimensional chemical space of the Protein Data Bank (PDB) in order to identify in a straightforward manner regular architectures containing the desired functionalities, which could be used as templates to guide the rational design of small natural-like scaffolds mimicking the targeted recognition site. The application of this rescaffolding strategy to the discovery of natural scaffolds incorporating a selection of functionalities of interleukin-10 receptor-1 (IL-10R1), which are relevant for its interaction with interleukin-10 (IL-10) has resulted in the de novo design of a new class of potent IL-10 peptidomimetic ligands.
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Ruiz-Gómez, Gloria, John C. Hawkins, Jenny Philipp, Georg Künze, Robert Wodtke, Reik Löser, Karim Fahmy i M. Teresa Pisabarro. "Rational Structure-Based Rescaffolding Approach to De Novo Design of Interleukin 10 (IL-10) Receptor-1 Mimetics". Public Library of Science, 2016. https://tud.qucosa.de/id/qucosa%3A30052.
Pełny tekst źródłaStreszczenie:
Tackling protein interfaces with small molecules capable of modulating protein-protein interactions remains a challenge in structure-based ligand design. Particularly arduous are cases in which the epitopes involved in molecular recognition have a non-structured and discontinuous nature. Here, the basic strategy of translating continuous binding epitopes into mimetic scaffolds cannot be applied, and other innovative approaches are therefore required. We present a structure-based rational approach involving the use of a regular expression syntax inspired in the well established PROSITE to define minimal descriptors of geometric and functional constraints signifying relevant functionalities for recognition in protein interfaces of non-continuous and unstructured nature. These descriptors feed a search engine that explores the currently available three-dimensional chemical space of the Protein Data Bank (PDB) in order to identify in a straightforward manner regular architectures containing the desired functionalities, which could be used as templates to guide the rational design of small natural-like scaffolds mimicking the targeted recognition site. The application of this rescaffolding strategy to the discovery of natural scaffolds incorporating a selection of functionalities of interleukin-10 receptor-1 (IL-10R1), which are relevant for its interaction with interleukin-10 (IL-10) has resulted in the de novo design of a new class of potent IL-10 peptidomimetic ligands.
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Howes, A. F. "The regulation of interleukin-10 and interleukin-12 in macrophages : investigating the differential regulation of IL-10 and IL-12 in C57BL/6 and BALB/c mice". Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1409974/.
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Pattern recognition receptors (PRR) detect microbial products and induce cytokines which shape the immunological response. Interleukin-12 (IL-12) is a proinflammatory cytokine important for the differentiation of T helper 1 (Th1) cells which produce IFN-γ to activate macrophages and eradicate intracellular pathogens. In contrast, interleukin-10 (IL-10) is an immunosuppressive cytokine that minimises immune-driven host pathology, but can also lead to defective pathogen clearance. The regulation of IL-10 and IL-12 is therefore of interest due to their central roles in the orchestration of an effective but regulated immune response. C57BL/6 and BALB/c mice differ significantly in their resistance to several pathogens. We observed that macrophages generated from these mice produce reciprocal levels of IL-10 and IL-12 in response to the bacterial ligands LPS and Pam3CSK4, which activate TLR4 and TLR2 respectively, and heat-killed Burkholderia pseudomallei, a Gram-negative bacterium which activates TLR2 and TLR4. We have investigated this differential cytokine production in order to further dissect the molecular mechanisms underlying the regulation of IL-10 and IL-12. Detailed analyses of protein production, signal transduction and transcriptional kinetics have identified a type I IFN dependent, but IL-27 independent mechanism for the differential production of IL-10 in LPS and heat-killed B.pseudomallei stimulated C57BL/6 and BALB/c macrophages. Microarray analysis of LPS stimulated C57BL/6 and BALB/c macrophages further revealed potential regulatory networks that may differ between these mouse strains. These findings highlight key pathways responsible for the regulation of IL-10 and IL-12, and may provide valuable information on factors contributing to the ability of C57BL/6 and BALB/c mice to clear bacterial infections.