Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 3957K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by von Knethen, A. Articles by Brüne, B. Search for Related Content PubMed PubMed Citation Articles by von Knethen, A. Articles by Brüne, B. Social Bookmarking                            What's this?

PPAR1 attenuates cytosol to membrane translocation of PKC to desensitize monocytes/macrophages

Institute of Biochemistry I, Faculty of Medicine, Johann Wolfgang Goethe University, 60590 Frankfurt, Theodor-Stern-Kai 7, Germany

Correspondence to Andreas von Knethen: v_knethen{at}zbc.kgu.de

Recently, we provided evidence that PKC depletion in monocytes/macrophages contributes to cellular desensitization during sepsis. We demonstrate that peroxisome proliferator–activated receptor (PPAR) agonists dose dependently block PKC depletion in response to the diacylglycerol homologue PMA in RAW 264.7 and human monocyte–derived macrophages. In these cells, we observed PPAR-dependent inhibition of nuclear factor-B (NF-B) activation and TNF- expression in response to PMA. Elucidating the underlying mechanism, we found PPAR1 expression not only in the nucleus but also in the cytoplasm. Activation of PPAR1 wild type, but not an agonist-binding mutant of PPAR1, attenuated PMA-mediated PKC cytosol to membrane translocation. Coimmunoprecipitation assays pointed to a protein–protein interaction of PKC and PPAR1, which was further substantiated using a mammalian two-hybrid system. Applying PPAR1 mutation and deletion constructs, we identified the hinge helix 1 domain of PPAR1 that is responsible for PKC binding. Therefore, we conclude that PPAR1-dependent inhibition of PKC translocation implies a new model of macrophage desensitization.

Abbreviations used in this paper: 15d-PGJ₂, 15-deoxy-^12,14-prostaglandin J₂; AF, activating function; CHX, cycloheximide; DAG, diacylglycerol; DBD, DNA-binding domain; DGK, DAG kinase ; EMSA, electrophoretic mobility shift assay; HEK, human embryonic kidney; IL, interleukin; LBD, ligand-binding domain; MCS, multicloning site; NF-B, nuclear factor-B; PPAR, peroxisome proliferator–activated receptor ; ROS, reactive oxygen species.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

• Ali, F. Y., Hall, M. G., Desvergne, B., Warner, T. D., Mitchell, J. A. (2009). PPAR{beta}/{delta} Agonists Modulate Platelet Function via a Mechanism Involving PPAR Receptors and Specific Association/Repression of PKC{alpha}-Brief Report. Arterioscler. Thromb. Vasc. Bio. 29: 1871-1873 [Abstract] [Full Text]  
• Ali, F. Y., Armstrong, P. C.J., Dhanji, A.-R. A., Tucker, A. T., Paul-Clark, M. J., Mitchell, J. A., Warner, T. D. (2009). Antiplatelet Actions of Statins and Fibrates Are Mediated by PPARs. Arterioscler. Thromb. Vasc. Bio. 29: 706-711 [Abstract] [Full Text]  
• Schock, S. C., Xu, J., Duquette, P. M., Qin, Z., Lewandowski, A. J., Rai, P. S., Thompson, C. S., Seifert, E. L., Harper, M.-E., Chen, H.-H. (2008). Rescue of Neurons from Ischemic Injury by Peroxisome Proliferator-Activated Receptor-{gamma} Requires a Novel Essential Cofactor LMO4. J. Neurosci. 28: 12433-12444 [Abstract] [Full Text]  
• Jennewein, C., Kuhn, A.-M., Schmidt, M. V., Meilladec-Jullig, V., von Knethen, A., Gonzalez, F. J., Brune, B. (2008). Sumoylation of Peroxisome Proliferator-Activated Receptor {gamma} by Apoptotic Cells Prevents Lipopolysaccharide-Induced NCoR Removal from {kappa}B Binding Sites Mediating Transrepression of Proinflammatory Cytokines. J. Immunol. 181: 5646-5652 [Abstract] [Full Text]  
• Lombardi, A., Cantini, G., Piscitelli, E., Gelmini, S., Francalanci, M., Mello, T., Ceni, E., Varano, G., Forti, G., Rotondi, M., Galli, A., Serio, M., Luconi, M. (2008). A New Mechanism Involving ERK Contributes to Rosiglitazone Inhibition of Tumor Necrosis Factor-{alpha} and Interferon-{gamma} Inflammatory Effects in Human Endothelial Cells. Arterioscler. Thromb. Vasc. Bio. 28: 718-724 [Abstract] [Full Text]  
• Maat, W., Ly, L. V., Jordanova, E. S., de Wolff-Rouendaal, D., Schalij-Delfos, N. E., Jager, M. J. (2008). Monosomy of Chromosome 3 and an Inflammatory Phenotype Occur Together in Uveal Melanoma. IOVS 49: 505-510 [Abstract] [Full Text]  
• Johann, A. M., Weigert, A., Eberhardt, W., Kuhn, A.-M., Barra, V., von Knethen, A., Pfeilschifter, J. M., Brune, B. (2008). Apoptotic Cell-Derived Sphingosine-1-Phosphate Promotes HuR-Dependent Cyclooxygenase-2 mRNA Stabilization and Protein Expression. J. Immunol. 180: 1239-1248 [Abstract] [Full Text]  
• von Knethen, A., Soller, M., Tzieply, N., Weigert, A., Johann, A. M., Jennewein, C., Kohl, R., Brune, B. (2007). PPAR{gamma}1 attenuates cytosol to membrane translocation of PKC{alpha} to desensitize monocytes/macrophages. JEM 204: i5-i5 [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents