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      Inhibition of TNF-α, Induced Cytokine and Adhesion Molecule

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          Abstract

          Activation of certain cytokines and adhesion molecules has been postulated being involved in the pathogenesis of experimental and human glomerulonephritis. In this study, we examined whether the transcription factor, nuclear factor ĸB (NFĸB), mediated the expression of these genes involved with the inflammatory response of mesangial cells by using transcription factor decoy oligodeoxynucleotides (ODN) to block NFĸB binding to the promoter site of its target genes. We hypothesized that the NFĸB decoy ODN can inhibit the coordinated activation of cytokines and adhesion molecules induced by TNF-α. Increased binding activity of NFĸB induced by TNF-α was effectively blocked by the NFĸB decoy ODN. TNF-α stimulated CAT expression, which was significantly inhibited by transfection of NFĸB, but not by scrambled decoy ODN. Of importance, NFĸB, but not scrambled decoy ODN, significantly attenuated the increase in RNA and protein levels of IL-1α, IL-1β, IL-6, ICAM-1 and VCAM-1 induced by TNF-α assessed by RT-PCR. Moreover, in vivo transfection of NFĸB decoy ODN inhibited expressions of these cytokines and adhesion molecules induced by TNF-α injection. These results suggest a novel therapeutic strategy for the treatment of glomerulonephritis using decoy ODN to block the binding of NFĸB, inhibiting the coordinated transactivation of the key cytokines and adhesion molecules, and thereby suppressing the inflammatory process.

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          Most cited references 7

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          Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia.

          Bacterial infection of the mammalian bloodstream can lead to overwhelming sepsis, a potentially fatal syndrome of irreversible cardiovascular collapse (shock) and critical organ failure. Cachectin, also known as tumour necrosis factor, is a macrophage-derived peptide hormone released in response to bacterial lipopolysaccharide, and it has been implicated as a principal mediator of endotoxic shock, although its function in bacterial sepsis is not known. Anaesthetized baboons were passively immunized against endogenous cachectin and subsequently infused with an LD100 dose of live Escherichia coli. Control animals (not immunized against cachectin) developed hypotension followed by lethal renal and pulmonary failure. Neutralizing monoclonal anti-cachectin antibody fragments (F(ab')2) administered to baboons only one hour before bacterial challenge protected against shock, but did not prevent critical organ failure. Complete protection against shock, vital organ dysfunction, persistent stress hormone release and death was conferred by administration of antibodies 2 h before bacterial infusion. These results indicate that cachectin is a mediator of fatal bacteraemic shock, and suggest that antibodies against cachectin offer a potential therapy of life-threatening infection.
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            NF-κB: A pleiotropic mediator of inducible and tissue-specific gene control

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              Functional analysis of the human vascular cell adhesion molecule 1 promoter

              The vascular cell adhesion molecule 1 (VCAM-1) is a 110-kD member of the immunoglobulin gene superfamily expressed on the surface of interleukin 1 beta- or tumor necrosis factor alpha (TNF)-stimulated endothelial cells. The cell surface protein functions as an inducible adhesion receptor for circulating mononuclear leukocytes and some tumor cells. We have previously characterized the genomic organization of the VCAM1 gene and described its chromosomal localization. In this report, the promoter of the VCAM1 gene is characterized. New transcription of the VCAM1 gene occurred when endothelial cells were treated with TNF. Fusion plasmids containing the 5' flanking sequence of the VCAM1 gene and the chloramphenicol acetyltransferase reporter gene were used to identify cis-acting sequences that direct the cytokine-induced transcription. When transfected into bovine aortic endothelial cells, constructs containing 755 bp of the 5' flanking sequence were induced by TNF. Within the cytokine-responsive region of the core promoter were functional NF-kappa B and GATA elements. Upstream of the core promoter, the VCAM1 5' flanking sequence contained a negative regulatory activity. NF-kappa B-mediated activation of VCAM1 gene expression may lead to endothelial expression of a mononuclear leukocyte adhesion molecule associated with initial events in the development of an atherosclerotic lesion.
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                Author and article information

                Journal
                EXN
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2001
                June 2001
                23 April 2001
                : 9
                : 3
                : 181-190
                Affiliations
                aDepartment of General Medicine, Osaka University Hospital, and Departments of bGeriatric Medicine and cGene Therapy Science, Osaka University Medical School, Suita, and dDepartment of Medical Biochemistry, Ehime University School of Medicine, Ehime, Japan
                Article
                52610 Exp Nephrol 2001;9:181–190
                10.1159/000052610
                11340302
                © 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: 7, References: 38, Pages: 10
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/52610
                Categories
                Original Paper

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