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 vario us autoimmune liver diseases strongly indicates that UDCA possesses im munomodulatory activities. Experimental evidence also supports this no tion, since, for example, UDCA has been shown to suppress secretion of IL-2, IL-4, and IFN-gamma from activated T lymphocytes, and Ig produc tion from B lymphocytes. To investigate the mechanical background of U DCA-mediated immunomodulation, we asked whether UDCA interacts with th e 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, i n which glucocorticoid receptor cDNA was stably integrated. In immunoc ytochemical analysis, we found that treatment with UDCA promoted the n uclear translocation of the glucocorticoid receptor in a ligand-indepe ndent fashion, which was further confirmed by immunoprecipitation assa ys. Moreover, the translocated glucocorticoid receptor demonstrated se quence-specific DNA binding activity. Transient transfection experimen ts revealed that treatment of the cells with UDCA marginally enhanced glucocorticoid-responsive gene expression. We also showed that UDCA su ppressed IFN-gamma-mediated induction of MHC class II gene expression via the glucocorticoid receptor-mediated pathway. Together, UDCA-depen dent promotion of translocation of the glucocorticoid receptor may be associated with, at least in part, its immunomodulatory action through glucocorticoid receptor-mediated gene regulation.