Corticosteroids antagonize TGF-β-Smad signaling in activated hepatic stellate cells

Aims: TGF-β signaling activates hepatic stellate cells (HSC) and promotes the development of liver fibrosis. Recent studies indicate that glucocorticoids and their receptors seem to antagonize TGF-β effects by interacting with the TGF-β-Smad pathway. However, the underlying mechanisms that mediate corticosteroid-TGF-β-interaction in HSC have not been clarified yet, but might be important for their antifibrotic effect. Methods: We studied the influence of corticosteroids (dexamethasone, hydrocortisone, and aldosterone) on TGF-β expression and signaling using adenoviral infection or transfection techniques, real-time PCR, Western blot and ELISA. Vice versa we also investigated the effect of Smads and TGF-β on the glucocorticoid mediated pathway in activated HSC and derived cells. Results: Our data show that glucocorticosteroids associated with their receptors decrease the bioavailability of TGF-β by down-regulation of mRNA transcription and reduction of TGF-β secretion. Adenoviral infection and transfection experiments with a Smad-binding-element-luciferase reporter construct showed a significantly reduced signaling in primary HSC and CFSCs, a HSC related cell line after dexamethasone or aldosterone treatment. Moreover, a dexamethasone-sensitive reporter construct showed that ectopic Smad 3 expression inhibits glucocorticoid receptor (GR) transactivation in CFSC and HEK 293, indicating a cross-talk of both transcription factors leading to a mutual transrepression. Like Smad 3, ectopic expression of Smad 2 and Smad 4 expression reduced dexamethasone-sensitive luciferase signal in HEK cells. We hypothesize that a homologous structure (MH2-domain) of the Smad‘s is involved in GR-Smad interaction. Conclusions: Taken together our data indicates a multifarious interaction between corticosteroids and TGF-β -Smad 3 pathway in activated HSC all directed to antagonize TGF-β signaling. This might be one molecular mechanism of the antifibrotic effects of glucocorticoids.

Literatur: Bolkenius U, Hahn D, Gressner AM, Breitkopf K, Dooley S, Wickert L. Glucocorticoids decrease the bioavailability of TGF-beta which leads to a reduced TGF-beta signaling in hepatic stellate cells. Biochem Biophys Res Commun. 2004 Dec 24;325(4):1264-70. Wickert L, Abiaka M, Bolkenius U, Gressner AM. Corticosteroids stimulate selectively transforming growth factor (TGF)-beta receptor type III expression in transdifferentiating hepatic stellate cells. J Hepatol. 2004 Jan;40(1):69-76.

Keywords: Smad, TGF-β, corticosteroide, cross-talk, glucocorticoid receptor