MOLECULAR MECHANISM OF IMMUNE REGULATION BY BILE ACIDS

UDCA已被广泛用作治疗胆固醇结石患者的药物，目前已被用于治疗各种肝病，包括原发性胆汁性肝硬化性胆管炎和病毒性肝炎。虽然这些UDGA作用的潜在分子机制在很大程度上是未知的，但这些不同的免疫调节特性至少部分地被免疫抑制类固醇糖皮质激素所共享。我们发现，UDCA在没有激动型配体的情况下激活了潜伏的GR物种，并促进了受体的核转位。转位的GR在体外能够与GRE结合，但用UDCA处理细胞后，糖皮质激素反应启动子的反式激活作用很弱。瞬时转基因研究还表明，UDCA的反式激活作用是由受体的配体结合域介导的。我们已经证明，UDCA既不与GR特异性结合，也不干扰地塞米松与GR的特异性相互作用。因此，我们推测UDCA与细胞膜相互作用产生二次信号，从而促进hsp90和GR的解离。因此，UDCA处理可能会产生一个可能的二次信号，它改变了适合HSP90解离和随后移位到细胞核的配体结合域的构象。因此，识别UDCA处理后的这种可能的次级信号，不仅有助于理解UDCA作用的分子机制(S)，而且有助于了解完整细胞中GR翻译后修饰的分子机制。

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.