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J. Biol. Chem., Vol. 276, Issue 50, 47371-47378, December 14, 2001
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From the Ursodeoxycholic acid (UDCA) is the
current mainstay of treatment for various liver diseases including
primary biliary cirrhosis. UDCA acts as a bile secretagogue,
cytoprotective agent, immunomodulator, and inhibitor of cellular
apoptosis. Despite this cumulative evidence of the cytoprotective and
immunosuppressive effects of UDCA, both the target molecule and pathway
of UDCA action remain unknown. We previously described that, in the
absence of glucocorticoid ligand, UDCA activates the glucocorticoid
receptor (GR) into DNA binding species but does not elicit its
transactivational function in a transient transfection assay. Here we
further studied the molecular mechanism of UDCA action and revealed
that the ligand binding domain of the GR is responsible for
UDCA-dependent nuclear translocation of the GR. Indeed, we
demonstrated that UDCA acts on the distinct region of the ligand
binding domain when compared with the classical GR agonist
dexamethasone, resulting in loss of coactivator recruitment and
differential regulation of gene expression by the GR. Our data clearly
indicated that UDCA, at least in part via activation of the GR,
suppresses NF-
Functional Modulation of the Glucocorticoid
Receptor and Suppression of NF-
B-dependent Transcription
by Ursodeoxycholic Acid*
§,¶,,, and
Second Department of Internal Medicine,
Asahikawa Medical College, 2-1-1, Midorigaoka-higashi, Asahikawa
078-8510 and ¶ Division of Clinical Immunology, Advanced Clinical
Research Center, Institute of Medical Science, University of Tokyo,
4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
B-dependent transcription through the
intervention of GR-p65 interaction. Together with the established
clinical safety of UDCA, we may propose that UDCA could be a
prototypical compound for development of a novel and selective GR modifier.
*
This work was supported in part by grants from the Ministry
of Education, Science, Technology, Sports, and Culture; the Ministry of
Health, Labor, and Welfare; the Takeda Science Foundation; the Suzuken
Memorial Foundation; the Japan Owner's Association; and the Cell
Science Research Foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Division of
Clinical Immunology, Advanced Clinical Research Center, Institute of
Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku,
Tokyo 108-8639, Japan. Tel./Fax: 81-3-5449-5547; E-mail: hirotnk@ims.u-tokyo.ac.jp.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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