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* Department of Rheumatology, Ghent University Hospital, Ghent, Belgium;
Laboratory of Eukaryotic Gene Expression and Signal Transduction, Department of Molecular Biology, Ghent University, Ghent, Belgium;
Laboratory for Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium;
Laboratory for Medicinal Chemistry, Ghent University, Ghent, Belgium; and
¶ Department of Rheumatology and Clinical Immunology, Kerckhoff Clinic and Justus-Liebig University Giessen, Bad Nauheim, Germany
The glucocorticoid receptor (GR) is a transcription factor regulating its target genes either positively, through direct binding to the promoter of target genes, or negatively by the interference with the activity of transcription factors involved in proinflammatory gene expression. The well-known adverse effects of glucocorticoids are believed to be mainly caused by their GR-mediated gene-activating properties. Although dimerization of GR is thought to be essential for gene-activating properties, no compound has yet been described which selectively imposes GR monomer formation and interference with other transcription factors. In the present study, we report on a GR-binding, plant-derived compound with marked dissociative properties in rheumatoid arthritis fibroblast-like synoviocytes, which are important effector cells in inflammation and matrix degradation in rheumatoid arthritis. In addition, these findings could be extended in vivo in murine collagen-induced arthritis, in which joint inflammation was markedly inhibited without inducing hyperinsulinemia. Therefore, we conclude that GR monomers are sufficient for inhibition of inflammation in vivo.
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1 This work was supported by grants from the Fund for Scientific Research-Flanders (Belgium), Concerted Action Grants from the Research Fund of Ghent University, and the German Research Society (Mu 1383) for U.M.-L., and in part by a research grant of Centocor. P.D. is a Research Assistant of the Fund for Scientific Research-Flanders (Belgium). K.D.B. and W.V.B. are Postdoctoral Fellows supported by the Fund for Scientific Research-Flanders. V.G. is a Predoctoral Fellow supported by the Innovatie door Wetenschap en Technologie Agency.
2 Address correspondence and reprint requests to Dr. Dirk Elewaut, Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. E-mail address: Dirk.Elewaut{at}UGent.be or Dr. Guy Haegeman, Laboratory for Eukaryotic Gene Expression and Signal Transduction, Department of Molecular Biology, Ghent University, K. L. Ledeganckstraat 35, B-9000 Ghent, Belgium. E-mail address: guy.haegeman{at}ugent.be
3 Abbreviations used in this paper: RA, rheumatoid arthritis; FLS, fibroblast-like synoviocyte; GC, glucocorticoid; GR, GC receptor; GRE, GC-responsive element; G6P, glucose-6-phosphatase; PEPCK, phospho-enol pyruvate carboxykinase; CpdA, compound A; CIA, collagen-induced arthritis; DEX, dexamethasone; DAPI, 4,6-diamidino-2-phenylindole; CII, collagen type II; HPRT, hypoxanthine phosphoribosyltransferase; MMP, matrix metalloproteinase; hPAP, human placental alkaline phosphatase; TAT, tyrosine aminotransferase; PCOLCE2, procollagen C-endopeptidase enhancer 2.
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