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      CD40L Activation in Circulating Platelets in Patients with Acute Coronary Syndrome

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          Abstract

          The CD40-CD40L interaction, which was initially shown to have important roles in the T cell-mediated activation of B cells during humoral immune responses, is now known to have roles in activation of endothelial cells, smooth muscle cells, and macrophages within atherosclerotic plaques. Recently, CD40L expression was found in activated platelets in the thrombus in vivo and CD40L was reported to be responsible for the platelet-mediated activation of endothelial cells in vitro. To investigate the activation status of platelets in coronary artery disease patients, we tested expression levels of CD40L, and platelet-endothelial cell adhesion molecule-1 (PECAM-1/CD31) in platelets isolated from peripheral blood, using flow cytometric analysis. Twenty-nine patients with acute coronary syndrome (10 acute myocardial infarction and 19 unstable angina patients) were compared with 14 normal subjects or 14 stable angina patients. In platelets isolated from normal subjects, the expression of CD40L was not detected in all subjects. In the patients with acute coronary syndrome, the average level of CD40L showed a significant increase (p = 0.0028), while stable angina patients did not have any increase when compared to normal subjects. Patients with more complex lesions or vessel occlusion tended to have a high platelet CD40L level compared to patients who do not. The expression levels of CD31 were increased in a small portion of the ACS patients. These data indicate that the rupture of plaque and subsequent formation of thrombus may lead to the activation of CD40L expression in circulating platelets of ACS patients.

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          Most cited references 8

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          CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells.

          CD40 ligand (CD40L, CD154), a transmembrane protein structurally related to the cytokine TNF-alpha, was originally identified on stimulated CD4+ T cells, and later on stimulated mast cells and basophils. Interaction of CD40L on T cells with CD40 on B cells is of paramount importance for the development and function of the humoral immune system. CD40 is not only constitutively present on B cells, but it is also found on monocytes, macrophages and endothelial cells, suggesting that CD40L has a broader function in vivo. We now report that platelets express CD40L within seconds of activation in vitro and in the process of thrombus formation in vivo. Like TNF-alpha and interleukin-1, CD40L on platelets induces endothelial cells to secrete chemokines and to express adhesion molecules, thereby generating signals for the recruitment and extravasation of leukocytes at the site of injury. Our results indicate that platelets are not only involved in haemostasis but that they also directly initiate an inflammatory response of the vessel wall.
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            Immune regulation by CD40 and its ligand GP39.

            Over the past three years, CD40 and its ligand (gp39, CD40L, TBAM) have been shown to be essential for humoral immune responses to thymus-dependent antigens. However, as the tissue distribution widens for those cells that express CD40 and gp39, we can now show that this ligand-receptor pair also plays an important role in the selection of self-reactive T cells in the thymus (central tolerance) and the regulation of tolerance in mature T cells (peripheral tolerance). Advances in our understanding of the molecular basis for CD40 biology is based in two areas of research. First, a major breakthrough in our understanding of how CD40 transduces biological events centers on the identification of a novel protein that binds to the cytoplasmic tail of CD40 and may act as a signal transducing molecule. Secondly, advances in molecular modeling and mutagenesis of this ligand-receptor pair have helped to identify the critical receptor/ligand contacts in the gp39/CD40 complex. Advances in each of these areas are discussed.
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              CD40 expression by human monocytes: regulation by cytokines and activation of monocytes by the ligand for CD40

              CD40 is a member of the tumor necrosis factor (TNF) receptor family of cell surface proteins and was originally described as a B cell restricted antigen. Treatment of primary human monocytes with granulocyte/macrophage colony-stimulating factor (GM-CSF), interleukin 3 (IL-3), or interferon gamma (IFN-gamma) resulted in the induction of CD40 mRNA and enhancement of cell surface protein expression. CD40 was found to mediate monocyte adhesion to cells expressing recombinant CD40 ligand. CD40 ligand-transfected cells provided a potent costimulus for monocyte TNF-alpha and IL-6 production in the presence of GM-CSF, IL-3, or IFN-gamma, and enhanced IL-8 production stimulated by GM-CSF or IL- 3. In addition, CD40 ligand-transfected cells acting in the absence of a costimulus induced monocytes to become tumoricidal against a human melanoma cell target. Collectively, these data indicate that CD40 ligand is pleiotropic with potent biological activity on monocytes.
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                Author and article information

                Journal
                CRD
                Cardiology
                10.1159/issn.0008-6312
                Cardiology
                S. Karger AG
                0008-6312
                1421-9751
                1999
                January 2000
                17 January 2000
                : 92
                : 1
                : 11-16
                Affiliations
                aCardiology Division, Samsung Medical Center, College of Medicine, Sung Kyun Kwan University, 50 Ilwon-dong, Kangnam-ku, Seoul, and bSamsung Biomedical Research Institute, 50 Ilwon-dong, Kangnam-ku, Seoul, Korea
                Article
                6940 Cardiology 1999;92:11–16
                10.1159/000006940
                10640791
                © 2000 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: 2, Tables: 1, References: 21, Pages: 6
                Categories
                General Cardiology, Basic Science

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