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.
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.
Tanaka
H
H
Second Department of Internal Medicine, Asahikawa Medical College, Japan.
Makino
Y
Y
Miura
T
T
Hirano
F
F
Okamoto
K
K
Komura
K
K
Sato
Y
Y
Makino
I
I
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002451:Cell Compartmentation; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation; D019084:Fluorescent Antibody Technique, Indirect; D005786:Gene Expression Regulation; D005802:Genes, MHC Class II; D005938:Glucocorticoids / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008024:Ligands; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D011994:Recombinant Proteins; D015398:Signal Transduction; D014158:Transcription, Genetic; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D008024:Ligands; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D011994:Recombinant Proteins; D014580:Ursodeoxycholic Acid; D003907:Dexamethasone; D007371:Interferon-gamma