Immunomodulating and anti-apoptotic action of ursodeoxycholic acid: where are we and where should we go?

Ursodeoxycholic acid (UDCA) is currently used in clinical practice worldwide not only for the dissolution of cholesterol gallstones, but also, mainly, to treat patients with chronic cholestatic liver diseases. However, the mechanisms of action of UDCA at the hepatocyte and cholangiolyte levels are still not completely understood. Much progress has been made from the first concept that the only mechanism of action of this bile acid was its choleretic action. One of the most fascinating mechanisms of action that was evoked for UDCA is its immunomodulating and anti-apoptotic action, which could, in part, be explained by its interaction with the glucocorticoid nuclear receptor at the hepatocyte level. Glucocorticoids, whose prototype is dexamethasone, are the major ligands of the glucocorticoid receptor. The biological effects of glucocorticoids are driven by a multiple-step reaction including binding of the steroid to the glucocorticoid receptor, DNA binding, receptor transformation, nuclear translocation and either positive or negative gene transactivation. In this issue of the journal, Weitzel and co-workers clearly demonstrated that the binding of UDCA to the glucocorticoid receptor is unspecific. Therefore, the anti-inflammatory, cytoprotective and anti-apoptotic actions of UDCA should be due not only to the mild interaction with the glucocorticoid receptor, but also to transactivation or transrepression of different cytoplasmic proteins that are involved in the survival pathway.