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      Proinflammatory Cytokines in Heart Disease

      a , b

      Blood Purification

      S. Karger AG

      TNF-α, IL-β, Ischemia, Atherosclerosis, Macrophages

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          Abstract

          Proinflammatory cytokines affect nearly all tissues and organ systems, and the vasculature is no exception. Although a considerable amount of research has focused on the role of the two most prominent proinflammatory cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF), in the pathogenesis of sepsis and septic shock, the role of these and other cytokines in the pathogenesis of atherosclerotic lesions of the coronary artery, the acute ischemic event associated with myocardial infarction, the progression of myocardiopathies or the loss of myocardial function in congestive heart failure is a relatively recent discovery. Moreover, there has also been significant investigation of the cardioprotective effects of cytokines. Most of the attention has focused on the acute coronary syndromes and the myocardial suppression that takes place as a result of acute ischemia. The potential for anticytokine-based therapies in treating heart disease is great. Parenteral TNF-α neutralization and IL-1 receptor blockade are presently used to treat rheumatoid arthritis. Two orally effective agents, the IL-1β-converting enzyme inhibitor and the mitogen-activating protein kinase p38 inhibitor, are currently being investigated in clinical trials.

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          Most cited references 3

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          Development of Chronic Inflammatory Arthropathy Resembling Rheumatoid Arthritis in Interleukin 1 Receptor Antagonist–Deficient Mice

          Interleukin (IL)-1 is a proinflammatory cytokine that plays important roles in inflammation, host defense, and the neuro-immuno-endocrine network. IL-1 receptor antagonist (ra) is an endogenous inhibitor of IL-1 and is supposed to regulate IL-1 activity. However, its pathophysiological roles in a body remain largely unknown. To elucidate the roles of IL-1ra, IL-1ra–deficient mice were produced by gene targeting, and pathology was analyzed on different genetic backgrounds. We found that all of the mice on a BALB/cA background, but not those on a C57BL/6J background, spontaneously developed chronic inflammatory polyarthropathy. Histopathology showed marked synovial and periarticular inflammation, with articular erosion caused by invasion of granulation tissues closely resembling that of rheumatoid arthritis in humans. Moreover, elevated levels of antibodies against immunoglobulins, type II collagen, and double-stranded DNA were detected in these mice, suggesting development of autoimmunity. Proinflammatory cytokines such as IL-1β, IL-6, and tumor necrosis factor α were overexpressed in the joints, indicating regulatory roles of IL-1ra in the cytokine network. We thus show that IL-1ra gene deficiency causes autoimmunity and joint-specific inflammation and suggest that IL-1ra is important in maintaining homeostasis of the immune system. Possible involvement of IL-1ra gene deficiency in RA will be discussed.
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            Arterial Inflammation in Mice Lacking the Interleukin 1 Receptor Antagonist Gene

            Branch points and flexures in the high pressure arterial system have long been recognized as sites of unusually high turbulence and consequent stress in humans are foci for atherosclerotic lesions. We show that mice that are homozygous for a null mutation in the gene encoding an endogenous antiinflammatory cytokine, interleukin 1 receptor antagonist (IL-1ra), develop lethal arterial inflammation involving branch points and flexures of the aorta and its primary and secondary branches. We observe massive transmural infiltration of neutrophils, macrophages, and CD4+ T cells. Animals appear to die from vessel wall collapse, stenosis, and organ infarction or from hemorrhage from ruptured aneurysms. Heterozygotes do not die from arteritis within a year of birth but do develop small lesions, which suggests that a reduced level of IL-1ra is insufficient to fully control inflammation in arteries. Our results demonstrate a surprisingly specific role for IL-1ra in the control of spontaneous inflammation in constitutively stressed artery walls, suggesting that expression of IL-1 is likely to have a significant role in signaling artery wall damage.
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              Interleukin-1[beta ] and tumor necrosis factor-[alpha ] release in normal and diseased human infrarenal aortas

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                Author and article information

                Journal
                BPU
                Blood Purif
                10.1159/issn.0253-5068
                Blood Purification
                S. Karger AG
                0253-5068
                1421-9735
                2001
                2001
                26 February 2001
                : 19
                : 3
                : 314-321
                Affiliations
                Departments of aMedicine and bSurgery, University of Colorado Health Sciences Center, Denver, Colo., USA
                Article
                46960 Blood Purif 2001;19:314–321
                10.1159/000046960
                11244192
                © 2001 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 1, References: 48, Pages: 8
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/46960
                Categories
                Proceedings of the 18th ISBP Meeting

                Cardiovascular Medicine, Nephrology

                IL-β, TNF-α, Macrophages, Ischemia, Atherosclerosis

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