Z Gastroenterol 2009; 47 - P311
DOI: 10.1055/s-0029-1241559

Galiellalactone inhibits pro-fibrogenic TGF-β effects in hepatic stellate cells

J Li 1, G Erkel 2, S Wölfel 3, C Meyer 1, J Dzieran 1, HL Weng 1, S Dooley 1
  • 1Universitätsmedizin Mannheim der Universität Heidelberg, Klinik II, Molekulare Gastroenterologie – Alkoholfolgeerkrankungen, Mannheim, Germany
  • 2Institut für Biotechnologie und Wirkstoff-Forschung, Universität Kaiserslautern, Kaiserslautern, Germany
  • 3Institut für Pharmazie und Molekulare Biotechnologie der Universität Heidelberg, Heidelberg, Germany

Background: Galiellalactone is a natural fungal metabolite isolated from the ascomycete Galiella rufa and was primary screened out as an inhibitor for IL-6/Stat3 signaling. It has been reported that galiellalactone induces apoptosis of phospho-Stat3 positive prostatic carcinoma cells and reduces mouse prostatic tumor xenograft growth. Recently we found that galiellalactone also inhibits the downstream signaling of TGF-β, a key regulator of liver fibrogenesis.

Aim: The aim of this study is to investigate whether galiellalactone is a potential drug against fibrogenesis in the liver.

Methods: Primary cultured hepatocytes and CFSC (an activated hepatic stellate cell (HSC) line isolated from cirrhotic rat liver induced by CCl4) were treated with galiellalactone or/and TGF-β. Reporter gene assays were performed to quantify transcriptional activity of P-Smad3. Western blot analysis were performed to measure pro-fibrogenic protein expression including connective tissue growth factor (CTGF) and a-smooth muscle actin (α-SMA) as well as apoptosis-related proteins, e.g. cleaved caspase-3 and Bcl-XL.

Results: Galiellalactone inhibits TGF-β induced CTGF and α-SMA expression in activated HSCs (CFSC). Further, the drug increases cleaved caspase 3 and decreases Bcl-XL protein expression in this cell type, but not in cultured mouse hepatocytes, indicating that galiellalactone selectively induces apoptosis in activated myofibroblasts. Besides inhibiting Stat3 posphorylation, galiellalactone decreases TGF-b mediated transcriptional activity of P-Smad3/4 in both CFSCs and hepatocytes.

Conclusions: Preliminary data suggest that galiellalactone displays anti-fibrotic activity in vitro, which is at least partially directed towards TGF-b signaling. Experiments in vivo will be carried out to observe whether this compound is a potential and suitable candidate for the treatment of liver fibrosis.