%0 Generic
%A Dropmann, Anne
%C Heidelberg
%D 2018
%F heidok:25713
%R 10.11588/heidok.00025713
%T TGF-β2 abundance in mice and men: A successful anti-TGF-β2 strategy in biliary-derived liver disease
%U https://archiv.ub.uni-heidelberg.de/volltextserver/25713/
%X TGF-β1 is a key player in the onset, the progress, and end stages of CLD promoting fibrogenesis and tumorigenesis. To date, the expression and function of TGF-β2 have not been investigated thoroughly in liver disease. In this thesis, we provide evidence that TgfB2 and not, as formerly known, only TgfB1 correlate with fibrogenesis and liver cancer development.  In a comparative analysis, we analyzed TgfB2 and TgfB1 expression and secretion in murine and human HSCs, hepatocytes, and HCC/hepatoblastoma cell lines. In various mouse models reflecting regeneration, acute and chronic liver disease, and human HCC sample cohorts, we demonstrated that both isoforms are expressed in different types of liver cells and that expression is elevated during the progression of CLD in mouse models in most cases. Although TgfB2 is mostly secreted at lower levels than TgfB1, its expression patterns largely follow similar profiles. However, the secretion of TgfB2 exceeded that of TgfB1 in some HCC cell lines. Our data indicates a more prominent implication of TgfB2 in biliary-derived liver disease models.  In this thesis, the anti-fibrotic and immunoregulatory effects of TgfB2 silencing in cholestatic MDR2-KO mice have been delineated for the first time. TgfB2 silencing by AONs specifically reduced collagen deposition and αSMA expression, but induced anti-fibrotic PparG expression. Accumulation of TGF-β2-specific AON was detected in macrophage-activated fibroblasts, LSEC, and activated HSCs in mice. This was in accordance with TgfB2 expression in these cell types. CD45-positive immune cell infiltration was reduced upon TGF-β2-specific AON treatment in the livers of MDR2-KO mice. Furthermore, TGF-β2 levels were found to be elevated and correlated with CD45-positive immune cell infiltration in PSC and PBC patients.  In summary, the data presented, provides a strong rationale to examine anti-TgfB2-directed treatment in patients with cholestatic liver damage as PSC or PBC.  Taken together, this thesis points towards TGF-β2 as a promising therapeutic target in CLD especially of biliary origin. It provides a direct rationale for TGF-β2-directed drug development an further suggests to initiate a clinical trial testing TGF-β2 inhibition in PSC and PBC patients.
%Z Oncotarget: 2016; 7:19499-19518