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      Increased Systemic Th17 Cytokines Are Associated with Diastolic Dysfunction in Children and Adolescents with Diabetic Ketoacidosis

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          Abstract

          Diastolic dysfunction suggestive of diabetic cardiomyopathy is established in children with T1DM, but its pathogenesis is not well understood. We studied the relationships of systemic inflammatory cytokines/chemokines and cardiac function in 17 children with T1DM during and after correction of diabetic ketoacidosis (DKA). Twenty seven of the 39 measured cytokines/chemokines were elevated at 6–12 hours into treatment of DKA compared to values after DKA resolution. Eight patients displayed at least one parameter of diastolic abnormality (DA) during acute DKA. Significant associations were present between nine of the cytokine/chemokine levels and the DA over time. Interestingly, four of these nine interactive cytokines (GM-CSF, G-CSF, IL-12p40, IL-17) are associated with a Th17 mediated cell response. Both the DA and CCL7 and IL-12p40, had independent associations with African American patients. Thus, we report occurrence of a systemic inflammatory response and the presence of cardiac diastolic dysfunction in a subset of young T1DM patients during acute DKA.

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          Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction.

          We have shown previously that T cells are required for the full development of angiotensin II-induced hypertension. However, the specific subsets of T cells that are important in this process are unknown. T helper 17 cells represent a novel subset that produces the proinflammatory cytokine interleukin 17 (IL-17). We found that angiotensin II infusion increased IL-17 production from T cells and IL-17 protein in the aortic media. To determine the effect of IL-17 on blood pressure and vascular function, we studied IL-17(-/-) mice. The initial hypertensive response to angiotensin II infusion was similar in IL-17(-/-) and C57BL/6J mice. However, hypertension was not sustained in IL-17(-/-) mice, reaching levels 30-mm Hg lower than in wild-type mice by 4 weeks of angiotensin II infusion. Vessels from IL-17(-/-) mice displayed preserved vascular function, decreased superoxide production, and reduced T-cell infiltration in response to angiotensin II. Gene array analysis of cultured human aortic smooth muscle cells revealed that IL-17, in conjunction with tumor necrosis factor-alpha, modulated expression of >30 genes, including a number of inflammatory cytokines/chemokines. Examination of IL-17 in diabetic humans showed that serum levels of this cytokine were significantly increased in those with hypertension compared with normotensive subjects. We conclude that IL-17 is critical for the maintenance of angiotensin II-induced hypertension and vascular dysfunction and might be a therapeutic target for this widespread disease.
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            Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications.

            The presence of a diabetic cardiomyopathy, independent of hypertension and coronary artery disease, is still controversial. This systematic review seeks to evaluate the evidence for the existence of this condition, to clarify the possible mechanisms responsible, and to consider possible therapeutic implications. The existence of a diabetic cardiomyopathy is supported by epidemiological findings showing the association of diabetes with heart failure; clinical studies confirming the association of diabetes with left ventricular dysfunction independent of hypertension, coronary artery disease, and other heart disease; and experimental evidence of myocardial structural and functional changes. The most important mechanisms of diabetic cardiomyopathy are metabolic disturbances (depletion of glucose transporter 4, increased free fatty acids, carnitine deficiency, changes in calcium homeostasis), myocardial fibrosis (association with increases in angiotensin II, IGF-I, and inflammatory cytokines), small vessel disease (microangiopathy, impaired coronary flow reserve, and endothelial dysfunction), cardiac autonomic neuropathy (denervation and alterations in myocardial catecholamine levels), and insulin resistance (hyperinsulinemia and reduced insulin sensitivity). This review presents evidence that diabetes is associated with a cardiomyopathy, independent of comorbid conditions, and that metabolic disturbances, myocardial fibrosis, small vessel disease, cardiac autonomic neuropathy, and insulin resistance may all contribute to the development of diabetic heart disease.
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              IL-21 and TGF-beta are required for differentiation of human T(H)17 cells.

              The recent discovery of CD4(+) T cells characterized by secretion of interleukin (IL)-17 (T(H)17 cells) and the naturally occurring regulatory FOXP3(+) CD4 T cell (nT(reg)) has had a major impact on our understanding of immune processes not readily explained by the T(H)1/T(H)2 paradigm. T(H)17 and nT(reg) cells have been implicated in the pathogenesis of human autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis. Our recent data and the work of others demonstrated that transforming growth factor-beta (TGF-beta) and IL-6 are responsible for the differentiation of naive mouse T cells into T(H)17 cells, and it has been proposed that IL-23 may have a critical role in stabilization of the T(H)17 phenotype. A second pathway has been discovered in which a combination of TGF-beta and IL-21 is capable of inducing differentiation of mouse T(H)17 cells in the absence of IL-6 (refs 6-8). However, TGF-beta and IL-6 are not capable of differentiating human T(H)17 cells and it has been suggested that TGF-beta may in fact suppress the generation of human T(H)17 cells. Instead, it has been recently shown that the cytokines IL-1beta, IL-6 and IL-23 are capable of driving IL-17 secretion in short-term CD4(+) T cell lines isolated from human peripheral blood, although the factors required for differentiation of naive human CD4 to T(H)17 cells are still unknown. Here we confirm that whereas IL-1beta and IL-6 induce IL-17A secretion from human central memory CD4(+) T cells, TGF-beta and IL-21 uniquely promote the differentiation of human naive CD4(+) T cells into T(H)17 cells accompanied by expression of the transcription factor RORC2. These data will allow the investigation of this new population of T(H)17 cells in human inflammatory disease.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                27 August 2013
                : 8
                : 8
                : e71905
                Affiliations
                [1 ]Section of Pediatric Endocrinology, Georgia Regents University (formerly Georgia Health Sciences University), Augusta, Georgia, United States of America
                [2 ]Medical Laboratory, Imaging, and Radiologic Sciences, Georgia Regents University, Augusta, Georgia, United States of America
                [3 ]Section of Pediatric Cardiology, The Brody School Of Medicine, East Carolina University, Greenville, North Carolina, United States of America
                [4 ]Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
                [5 ]Section of Pediatric Critical Care, The Brody School of Medicine, East Carolina University, Greenville, North Carolina, United States of America
                [6 ]Section of Pediatric Endocrinology, The Brody School of Medicine, East Carolina University, Greenville, North Carolina, United States of America
                [7 ]The W. Harry Feinstone Department of Molecular Microbiology & Immunology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America
                New York University, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: WH IF GH GP D. Hannon NR. Performed the experiments: IF GH PF D. Hannon MT CB D. Haislip CK. Analyzed the data: WH GP D. Hannon DC NR PF. Contributed reagents/materials/analysis tools: D. Hannon GH NR WH DC MT. Wrote the paper: WH DC D. Hannon GP IF.

                Article
                PONE-D-13-17055
                10.1371/journal.pone.0071905
                3754936
                24013901
                059c862f-1bb2-48e9-ae45-eaee043c4ba7
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 26 April 2013
                : 4 July 2013
                Page count
                Pages: 13
                Funding
                The study was funded by Johns Hopkins Center for Autoimmune Disease Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine
                Cardiovascular
                Pediatric Cardiology
                Clinical Immunology
                Autoimmune Diseases
                Diabetes Mellitus Type 1
                Immune System
                Cytokines
                Immunity
                Inflammation
                Endocrinology
                Diabetic Endocrinology
                Diabetes Mellitus Type 1
                Pediatrics
                Pediatric Cardiology
                Radiology
                Diagnostic Radiology
                Echocardiography

                Uncategorized
                Uncategorized

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