| Research Abstract |
UDCA, which has widely been used as a therapeutic drug for patients with cholesterol gall stones, is currently indicated for various liver diseases including primary biliary cirrhosis, primary sclerosing cholangitis, and viral hepatitis. Although underlying molecular mechanism for these UDGA action are largely unknown, these diverse immunomodulating properties are, at least in part, shared by immunosuppressive steroid glucocorticoids. We showed that UDCA activates the latent GR species in the absence of agonistic ligands, and promotes nuclear translocation of the receptor. The translocated GR is shown to be able to bind GRE in vitro, however, transactivation of the glucocorticoid-responsive promoter was very weakly induced after treatment of the cells with UDCA.Transient transfection studies also revealed that transactivational effect of UDCA was mediated by the ligand binding domain of the receptor We have shown that UDCA does not either specifically bind to GR or interfere with specific interaction between dexamethasone and GR in CHOpMTGR cells. Thus, we may speculate that UDCA interact with the cell membrane to generate secondary signal, which promotes dissociation of hsp9O and GR.Therefore, treatment with UDCA may generate a putative secondary signal, which alters the conformation of the ligand binding domain suitable for dissociation of hsp90 and subsequent translocation to the nucleus. To identify such putative secondary signal after treatment with UDCA, therefore, will facilitate understanding not only molecular mechanism(s) of UDCA action, but that for posttranslational modification of GR in intact cells as well.
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