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Ligand-independent activation of the glucocorticoid receptor by ursodeoxycholic acid. Repression of IFN-gamma-induced MHC class II gene expression via a glucocorticoid receptor-dependent pathway

Item Type:Article
Title:Ligand-independent activation of the glucocorticoid receptor by ursodeoxycholic acid. Repression of IFN-gamma-induced MHC class II gene expression via a glucocorticoid receptor-dependent pathway
Creators Name:Tanaka, H. and Makino, Y. and Miura, T. and Hirano, F. and Okamoto, K. and Komura, K. and Sato, Y. and Makino, I.
Abstract:The therapeutic effectiveness of ursodeoxycholic acid (UDCA) for various autoimmune liver diseases strongly indicates that UDCA possesses immunomodulatory activities. Experimental evidence also supports this notion, since, for example, UDCA has been shown to suppress secretion of IL-2, IL-4, and IFN-gamma from activated T lymphocytes, and Ig production from B lymphocytes. To investigate the mechanical background of UDCA-mediated immunomodulation, we asked whether UDCA interacts with the intracellular signal transduction pathway, especially whether it is involved in immunosuppressive glucocorticoid hormone action. For this purpose, we used a cloned Chinese hamster ovary cell line, CHOpMTGR, in which glucocorticoid receptor cDNA was stably integrated. In immunocytochemical analysis, we found that treatment with UDCA promoted the nuclear translocation of the glucocorticoid receptor in a ligand-independent fashion, which was further confirmed by immunoprecipitation assays. Moreover, the translocated glucocorticoid receptor demonstrated sequence-specific DNA binding activity. Transient transfection experiments revealed that treatment of the cells with UDCA marginally enhanced glucocorticoid-responsive gene expression. We also showed that UDCA suppressed IFN-gamma-mediated induction of MHC class II gene expression via the glucocorticoid receptor-mediated pathway. Together, UDCA-dependent promotion of translocation of the glucocorticoid receptor may be associated with, at least in part, its immunomodulatory action through glucocorticoid receptor-mediated gene regulation.
Keywords:Immunologic Adjuvants, Base Sequence, CHO Cells, Cell Compartmentation, Dexamethasone, DNA-Binding Proteins, Down-Regulation, Gene Expression Regulation, Genetic Transcription, Glucocorticoid Receptors, Glucocorticoids, Indirect Fluorescent Antibody Technique, Interferon-gamma, Ligands, Messenger RNA, MHC Class II Genes, Molecular Sequence Data, Recombinant Proteins, Signal Transduction, Ursodeoxycholic Acid, Animals, Cricetinae
Source:Journal of Immunology
ISSN:0022-1767
Publisher:American Association of Immunologists (U.S.A.)
Volume:156
Number:4
Page Range:1601-1608
Date:15 February 1996
Official Publication:http://www.jimmunol.org/cgi/content/abstract/156/4/1601
PubMed:View item in PubMed

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