Glucocorticoids decrease the bioavailability of TGF-β which leads to a reduced TGF-β signaling in hepatic stellate cells

Glucocorticoids bound to their receptors transmit information, which regulates numerous physiological and pathophysiological responses, amongst others glucose metabolism, wound healing, inflammation, and stress, either directly as transcription factors by binding DNA elements of target genes or indirectly by protein–protein interactions with other transcription factors. TGF-β, a key factor in activation of hepatic stellate cells (HSC), induces production of extracellular matrix, this being a prerequisite for the development of liver fibrosis. Glucocorticoids and their receptors may provide a crosstalk with the TGF-β-Smad signaling pathway by antagonizing TGF-β effects. We studied the influence of glucocorticoids on the TGF-β isoform and Smad mRNA expression, TGF-β secretion, and signaling in activated HSC using gene-specific real-time PCR, ELISA, and transfection techniques. Dexamethasone treatment reduces TGF-β mRNA transcription in a time-dependent manner. Activated HSC produce TGF-β and secrete it into the cell culture medium. After dexamethasone treatment, TGF-β secretion into the medium is reduced dose-dependently but restorable by mifepristone. Further, we found that reduced secretion of endogenous TGF-β is accompanied by a reduced TGF-β signal. Additionally, reporter gene analysis after adenoviral infection with a recombinant virus encoding a Smad-binding-element showed that TGF-β-Smad signaling is significantly down-regulated by dexamethasone in primary HSC and CFSC, a HSC related cell line. Our data suggest that glucocorticoids inhibit TGF-β expression, prevent TGF-β from efficient secretion, and finally lead to reduced TGF-β signaling in primary HSC.