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      Interleukin 12 Upregulates the Release of Vascular Permeability Factor by Peripheral Blood Mononuclear Cells from Patients with Lipoid Nephrosis

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          Abstract

          The vascular permeability factor (VPF) is a lymphokine that has been shown to play a role in lipoid nephrosis (LN). Prior studies have shown that interleukin (IL) 12 promotes T helper type 1 differentiation and enhances production of T helper type 1 cytokines such as gamma interferon and IL-2. We, therefore, investigated the effects of recombinant human IL-12 on the release of VPF by peripheral blood mononuclear cells (PBMC) from LN patients. The VPF activity was measured according to the method of Ovary, with minor modifications. The goal of the present study was to examine the importance of IL-12 in concanavalin A induced VPF release in vitro. The levels of VPF were measured in a group of healthy subjects, LN patients with or without the nephrotic syndrome, and patients suffering from IgA nephropathy. There was a significantly increased concanavalin A induced release of VPF in LN and IgA nephropathy patients with nephrotic syndrome as compared with normal controls. Recombinant human IL-12 was found to enhance VPF release in a dose-dependent manner. Neutralization of endogenously produced IL-12 by anti-IL-12 antibody resulted in a decreased release of VPF by LN PBMC. These data indicate that endogenously produced IL-12 functions as a costimulatory molecule in vitro. Our data show that IL-12 can upregulate the release of VPF derived from LN PBMC. Thus IL-12 might be a potent adjuvant for inducing VPF. Therefore, IL-12 antagonists may interfere with newly initiated and ongoing VPF release associated with nephrotic syndrome.

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          Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma- production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells

          Natural killer cell stimulatory factor or interleukin 12 (NKSF/IL-12) is a heterodimeric cytokine produced by monocytes/macrophages, B cells, and possibly other accessory cell types primarily in response to bacteria or bacterial products. NKSF/IL-12 mediates pleiomorphic biological activity on T and NK cells and, alone or in synergy with other inducers, is a powerful stimulator of interferon gamma (IFN- gamma) production. IL-10 is a potent inhibitor of monocyte-macrophage activation, that inhibits production of tumor necrosis factor alpha (TNF-alpha), IL-1 and also IFN-gamma from lymphocytes acting at the level of accessory cells. Because TNF-alpha and IL-1 are not efficient inducers of IFN-gamma, the mechanism by which IL-10 inhibits IFN-gamma production is not clear. In this paper, we show that IL-10 is a potent inhibitor of NKSF/IL-12 production from human peripheral blood mononuclear cells activated with Staphylococcus aureus or lipopolysaccharide (LPS). Both the production of the free NKSF/IL-12 p40 chain and the biologically active p70 heterodimer are blocked by IL- 10. NKSF/IL-12 p40 chain mRNA accumulation is strongly induced by S. aureus or LPS and downregulated by IL-10, whereas the p35 mRNA is constitutively expressed and only minimally regulated by S. aureus, LPS, or IL-10. Although IL-10 is able to block the production of NKSF/IL-12, a powerful inducer of IFN-gamma both in vitro and in vivo, the mechanism of inhibition of IFN-gamma by IL-10 cannot be explained only on the basis of inhibition of NKSF/IL-12 because IL-10 can partially inhibit IFN-gamma production induced by NKSF/IL-12, and also, the IFN-gamma production in response to various stimuli in the presence of neutralizing antibodies to NKSF/IL-12. Our findings that antibodies against NKSF/IL-12, TNF-alpha, or IL-1 beta can significantly inhibit IFN-gamma production in response to various stimuli and that NKSF/IL-12 and IL-1 beta can overcome the IL-10-mediated inhibition of IFN-gamma, suggest that IL-10 inhibition of IFN-gamma production is primarily due to its blocking production from accessory cells of the IFN-gamma- inducer NKSF/IL-12, as well as the costimulating molecule IL-1 beta.
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            Author and article information

            Journal
            NEF
            Nephron
            10.1159/issn.1660-8151
            Nephron
            S. Karger AG
            1660-8151
            2235-3186
            1998
            April 1998
            26 March 1998
            : 78
            : 4
            : 403-409
            Affiliations
            2nd Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
            Article
            44968 Nephron 1998;78:403–409
            10.1159/000044968
            9578066
            © 1998 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: 4, Tables: 1, References: 16, Pages: 7
            Product
            Self URI (application/pdf): https://www.karger.com/Article/Pdf/44968
            Categories
            Original Paper

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