Tauroursodeoxycholic acid shows converse effects on TGF-β-Smad 3 signaling in liver cells

Aims: Tauroursodeoxycholic acid (TUDCA) has a positive effect on cholestatic liver disease especially with autoimmune etiology, which seems to be further enhanced by a combination with locally active corticosteroids. TGF-β, a master cytokine of liver fibrosis, activates hepatic stellate cells (HSC) and induces extracellular matrix components in vivo and in vitro. Our recent studies with HSC showed that glucocorticoids (GC) and their receptor (GR) interact with the TGF-β-Smad 3 pathway, which leads to an inhibition of TGF-β effects. Aim of the present study was to investigate if TUDCA interacts with TGF-β-Smad 3 signaling and if there is any cooperation with GC.

Methods: We studied the influence of TUDCA and glucocorticoids on TGF-β target gene expression in activated HSC, Hep-G2 and CFSC (HSC derived cell line) using real-time PCR, transfection techniques, and Western blot.

Results: The co-treatment of CFSC with dexamethasone/budesonide and TUDCA enhance the inhibitory effect of the GC on TGF-β induced Smad 3 mediated reporter signaling. Whereas inhibitory action of dexamethasone on TGF-β could be restored by mifepristone, the GC antagonist had no influence on budesonide effect. Our data indicate that dexamethasone and budesonide bind their receptors at separate binding sites. Conversely, TUDCA alone stimulates TGF-β sensitive reporter response in HSC. This results could not be transferred to TGF-β target genes, which were modulated individually in activated HSC. HSC treated 16 hours with TUDCA or GC show a reduced collagen 1 and an induced CTGF protein expression.

Conclusions: Our data show for the first time the oppositional effects of TUDCA on TGF-β-Smad 3 signaling in activated HSC, which seem to be dependent on glucocorticoid presence and other unknown factors.