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The expression of interleukin 20 and its role in rheumatoid arthritis
Yadollahi, Benjamin ; Šenolt, Ladislav (advisor) ; Krulová, Magdaléna (referee)
Rheumatoid arthritis (RA) is a chronic autoimmune disease that is associated with formation of autoantibodies, activation of inflammatory cascade and up-regulation of several cytokines. These processes lead to persistent synovial inflammation, joint damage and systemic manifestations. The aim of this diploma thesis is to characterize the role of a novel cytokine interleukin-20 (IL-20) in the pathogenesis of RA and to investigate its involvement in different stages of the disease as a potential surrogate biomarker. In this work, several methods including Enzyme-Linked Immunosorbent Assay (ELISA), Immunohistochemistry and Real-Time quantitative Polymerase Chain Reaction (RT-qPCR) have been employed. We demonstrated increased expression of IL-20 in the synovial tissue of RA compared with control osteoarthritis (OA) patients. Along with the up-regulation at sites of inflammation, concentrations of IL-20 were higher in the synovial fluid compared with circulating levels of IL-20. Furthermore, serum and synovial fluid IL-20 levels significantly correlated with RA disease activity. Synthesis of IL-20 was significantly increased in peripheral blood mononuclear cells (PBMCs) and synovial fibroblasts upon stimulation with some TLR ligands and pro-inflammatory cytokines. Although not regulating PBMCs functions in...
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The role of S100 proteins in the pathogenesis of rheumatic diseases
Andrés Cerezo, Lucie ; Šenolt, Ladislav (advisor) ; Hrnčíř, Zbyněk (referee) ; Horák, Pavel (referee)
Introduction: Recent findings and better understanding to the pathogenesis of rheumatic diseases contributed to the development of biological therapies targeting cytokines and immune cells. Several S100 proteins exert cytokine-like effects and participate in the regulation of the inflammatory process. The aim of this work was to study the role of selected S100 proteins in the activity and in the pathogenesis of the rheumatic diseases. Results: Our data show for the first time an association of S100A4 proteinwith RA disease activity and decrease of the bioactive form, but not the total amount of S100A4, after aplication of tumour necrosis factor (TNF) blocking biologic therapy in patients with RA. We demonstrated that in vitro S100A4 acts as a potent pro-inflammatory mediator inducing production of TNFα, interleukin (IL)-1β and IL-6 in PBMCs via Toll-like receptor 4 (TLR-4), transcription factor NFκB and tyrosine kinases erk1/2 and p38. Moreover, S100A4 can play an important role in the pathogenesis of inflammatory myopathies. S100A4 is present in the inflammatory infiltrate of the affected muscles and in the regenerating muscles and may act as a cytokine-like factor indirectly promoting muscle fiber damage by stimulating mononuclear cells to increase the synthesis of pro-inflammatory cytokines. We...
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New cytokines in the pathogenesis of rheumatic diseases
Filková, Mária ; Šenolt, Ladislav (advisor) ; Hrnčíř, Zbyněk (referee) ; Horák, Pavel (referee)
Background: An imbalance between pro- and anti- inflammatory cytokine activities favors the induction of autoimmunity, chronic inflammation and joint damage in patients with rheumatoid arthritis (RA). Adipokines are bioactive proteins that are important regulators of inflammation. IL-35 is a new cytokine involved in the inflammatory processes in mouse models and is of unknown function in humans. The aim of the work was to study the levels and role of several adipokines and IL-35 in the joint and blood compartment and the association with the disease activity in patients with RA or other rheumatic diseases. Results: We found increased levels of adiponectin in serum of patients with erosive osteoarthritis (OA) of the hand, differential regulation of new adipokines vaspin and omentin in synovial fluid of patients with RA compared with OA and the effect of therapy using TNFα inhibitor on the expression profile of adipokines in subcutaneous adipose tissue of RA patients. B cell depletion therapy in RA resulted in decrease of serum levels of visfatin that correlated with following change of disease activity. The levels of IL-35 in synovial fluid are significantly higher in RA than in OA and correlate with the disease activity and functional status. IL-35 subunits p35 and EBI3 are overexpressed in RA...
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Novel metabolic regulators and proinflammatory factors in the etiopathogenesis of type 2 diabetes mellitus and obesity: the influence of pharmacological and dietary interventions
Mráz, Miloš ; Haluzík, Martin (advisor) ; Šenolt, Ladislav (referee) ; Hainer, Vojtěch (referee)
NOVEL METABOLIC REGULATORS AND PROINFLAMMATORY FACTORS IN THE ETIOPATHOGENESIS OF TYPE 2 DIABETES MELLITUS AND OBESITY: THE INFLUENCE OF PHARMACOLOGICAL AND DIETARY INTERVENTIONS MUDr. Miloš Mráz Doctoral Thesis ABSTRACT (EN) Identifying novel factors involved in the etiopathogenesis of obesity, diabetes mellitus and their complications has become one of the primary scopes of metabolic research in the last years. The aim of the present study was to evaluate the role of recently discovered metabolic and inflammatory regulators including fibroblast growth factors 19 and 21 and chemotactic cytokines in the development of obesity and type 2 diabetes mellitus (DM2). A total number of 182 patients were included into the study. They were divided into 3 groups - patients with obesity but without type 2 diabetes mellitus, individuals with obesity and type 2 diabetes mellitus and healthy control normal-weight subjects. Selected interventions included 2 to 3 weeks of very-low-calorie diet (VLCD - energy content 2500 kJ/day), 3 months of administration of PPARα receptor agonist fenofibrate and acute hyperinsulinemia during hyperinsulinemic isoglycemic clamp. Our results indicate that the increase of circulating FGF-21 levels after VLCD and fenofibrate treatment could contribute to positive metabolic effects of these...
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Regulation of Novel cytokines in Autoimmune Rheumatic Diseases
Yadollahi, Benjamin ; Šenolt, Ladislav (advisor) ; Krulová, Magdaléna (referee)
A large number of cytokines are expressed in the feet and hands joints of patients with Rheumatoid arthritis. It is necessary to study the new cytokines which may help in prognosis and diagnosis of this autoimmune disease. Omentin1 and Interleukin 20 are the new cytokines and their expressions may have a role in the expression of proinflammatory cytokines; IL-1, IL-6 and TNF, in different cell tissues such as synovial fibroblasts, chondrocytes, peripheral blood mononuclear cells and, sera. It is conceivable that these biomarkers may be used in biological therapies.
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The role of adipose tissue in endothelial dysfunction, etherosclerosis and other complications of metabolic syndrome: influence of diet and pharmacotherapy
Doležalová, Radka ; Haluzík, Martin (advisor) ; Šenolt, Ladislav (referee) ; Kábrt, Jan (referee)
The metabolic effects of obesity have made this disease one of the most common risk factors for diabetes, hypertension, and atherosclerosis. Adipose tissue is now recognized as an active secretory and immune organ. Chronic inflammation is a common feature of the obesity, and inflammatory signals may originate within visceral adipose tissue as this fat depot expands in response to chronic positive energy balance. Both adipocytes and macrophages within fat secrete numerous hormones and cytokines that have local effects on WAT physiology but also systemic effects on other organs and may markedly contribute to the development of pathophysiological disorders associated with metabolic syndrome. On the contrary, leanness as well as significant weight reduction in obese patients increases production and circulating levels of metabolically beneficial factors and decreases production of proinflammatory and insulin resistance-inducing factors. Endothelial dysfunction and inflammation are important signs of vascular risk and worsened prognosis in patients with metabolic syndrome and type 2 diabetes. Measures of endothelial function remain invaluable for research into disease mechanism and response to new therapies. An interesting area of ongoing investigation is the role of thiazolidinediones in improving endothelial...
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Role of Adipokines and Ghrelin in Normal and Nutritionally Modulated Adjuvant Ar thritis in Rats
Štofková, Andrea ; Jurčovičová, Jana (advisor) ; Hainer, Vojtěch (referee) ; Šenolt, Ladislav (referee)
Autoimmune chronic inflammatory diseases, affecting as much as 5-7% of the general population, represent a considerable portion of human morbidity and many are known to be heritable. The clinical observations strongly suggest that even in genetically predisposed person, some trigger (an environmental exposure or change in the internal environment) is required for initiation of autoreactivity. However, for most autoimmune diseases, the trigger is unknown. Over the last decade, it has become apparent that obesity is an enhancer of chronic inflammation, and white adipose tissue products - adipokines and gastric hormone ghrelin have attracted attention for their immunomodulatory roles representing promising avenues for pharmacotherapy of autoimmune chronic inflammatory diseases. The purpose of this dissertation was to extend our understanding of the roles of adipokines and ghrelin in chronic inflammation using an experimental model of rheumatoid arthritis, adjuvant arthritis (AA) in rats. The chronic inflammation was studied under the condition of (a) normofeeding, (b) overfeeding (using a model of early-life diet-induced obesity, comprising small litter size and high-fat diet consumption) and (c) 40% foodrestriction to reveal to what extent nutritional factors affect adipokine and ghrelin levels and...
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název v anglickém jazyce není uveden
Šenolt, Ladislav ; Pavelka, Karel (advisor) ; Rovenský, Jozef (referee) ; Pokorný, Jaroslav (referee)
Rheumatoid arthritis (RA) and osteoarthritis (OA) represent the most common forms of musculosceletal disorders that affect diarthrodial joints, lead to joint damage and disability. Extra-articular manifestations accompanied the joint disease only in RA. Diagnosis of both conditions most commonly bears on the conventional radiography. Mostly in OA, radiographic changes often occur late in the disease and are largely irreversible. Molecular markers could reflect joint damage, inflammation, or immune response. Current investigation revealed potential uses of molecular markers, ranging from understanding pathogenesis of the diseases to predicting and monitoring the outcome of the treatment. The aim of the thesis was to analyze several biochemical markers in serum, synovial fluid and synovial tissue samples from patients with RA and OA. and to evaluate their diagnostic and predictive values as well as their contribution to the pathogenesis of the diseases. We found increased serum pentosidine concentrations in OA patients that were ol a predictive value of the joint space narrowing in OA of the knee joint and correlation between pentosidine and cartilage oligomeric matrix protein (COMP) in synovial fluid that make pentosidine one of the new potential biomarkers of the OA. Scrum level of COMP was similar among...
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