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      Effect of 15d-PGJ 2 on the Expression of CD40 and RANTES Induced by IFN-γ and TNF-α on Renal Tubular Epithelial Cells (HK-2)

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          Background/Aims: Recent evidence shows that peroxisome proliferator-activated receptor-γ (PPAR-γ) ameliorates a variety of inflammatory conditions. CD40 is a co-stimulatory molecule and its ligation induces production of different proinflammatory cytokines including RANTES (regulated upon activation, normal T cell expressed), which are considered as important factors in the initiation and maintenance of inflammatory response. The aim of this study was to investigate the effect of PPAR-γ on CD40 and RANTES production on cultured human renal proximal tubular epithelial (HK-2) cells. Methods: HK-2 cells were maintained under defined in vitro conditions and treated with either PPAR-γ agonist 15-deoxy-12,14-prostaglandin J<sub>2</sub> (15d-PGJ<sub>2</sub>) or 15d-PGJ<sub>2</sub> + PPAR-γ antagonist GW9662, and then stimulated with a combination of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). The CD40 and RANTES levels were investigated. Results: HK-2 cells expressed low levels of CD40 and RANTES. Activation of HK-2 cells by combined treatment of TNF-α and IFN-γ results in strong synergistic effects on the expression of CD40 and the secretion of RANTES. 15d-PGJ<sub>2</sub> significantly decreased CD40 and RANTES expression and GW9662 partly abrogated the inhibition of 15d-PGJ<sub>2</sub> on CD40 and RANTES. Conclusion: 15d-PGJ<sub>2</sub> significantly decreased CD40 and RANTES expression in HK-2 cells, which were partially mediated by PPAR-γ-dependent pathways. These results point to PPAR-γ as a remarkable new target in the prevention of tubular inflammatory injury associated with renal disease.

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          Most cited references 22

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          Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase.

          NF-kappaB is a critical activator of genes involved in inflammation and immunity. Pro-inflammatory cytokines activate the IkappaB kinase (IKK) complex that phosphorylates the NF-kappaB inhibitors, triggering their conjugation with ubiquitin and subsequent degradation. Freed NF-kappaB dimers translocate to the nucleus and induce target genes, including the one for cyclo-oxygenase 2 (COX2), which catalyses the synthesis of pro-inflammatory prostaglandins, in particular PGE. At late stages of inflammatory episodes, however, COX2 directs the synthesis of anti-inflammatory cyclopentenone prostaglandins, suggesting a role for these molecules in the resolution of inflammation. Cyclopentenone prostaglandins have been suggested to exert anti-inflammatory activity through the activation of peroxisome proliferator-activated receptor-gamma. Here we demonstrate a novel mechanism of antiinflammatory activity which is based on the direct inhibition and modification of the IKKbeta subunit of IKK. As IKKbeta is responsible for the activation of NF-kappaB by pro-inflammatory stimuli, our findings explain how cyclopentenone prostaglandins function and can be used to improve the utility of COX2 inhibitors.
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            Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb.

            Members of the Hedgehog (Hh) and Wnt/Wingless (Wg) families of secreted proteins control many aspects of growth and patterning during animal development. Hh signal transduction leads to increased stability of a transcription factor, Cubitus interruptus (Ci), whereas Wg signal transduction causes increased stability of Armadillo (Arm/beta-catenin), a possible co-factor for the transcriptional regulator Lef1/TCF. Here we describe a new gene, slimb (for supernumerary limbs), which negatively regulates both of these signal transduction pathways. Loss of function of slimb results in a cell-autonomous accumulation of high levels of both Ci and Arm, and the ectopic expression of both Hh- and Wg- responsive genes. The slimb gene encodes a conserved F-box/WD40-repeat protein related to Cdc4p, a protein in budding yeast that targets cell-cycle regulators for degradation by the ubiquitin/proteasome pathway. We propose that Slimb protein normally targets Ci and Arm for processing or degradation by the ubiquitin/proteasome pathway, and that Hh and Wg regulate gene expression at least in part by inducing changes in Ci and Arm, which protect them from Slimb-mediated proteolysis.
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              The PPARs:  From Orphan Receptors to Drug Discovery†


                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                September 2006
                15 September 2006
                : 26
                : 4
                : 356-362
                Department of Nephrology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, PR China
                94735 Am J Nephrol 2006;26:356–362
                © 2006 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: 3, Tables: 1, References: 32, Pages: 7
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/94735
                Original Report: Laboratory Investigation


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