TY  - JOUR
A1  - Dropmann, Anne
A1  - Dooley, Steven
A1  - Dewidar, Bedair
A1  - Hammad, Seddik
A1  - Dediulia, Tatjana
A1  - Werle, Julia
A1  - Hartwig, Vanessa
A1  - Ghafoory, Shahrouz
A1  - Wölfl, Stefan
A1  - Korhonen, Hanna
A1  - Janicot, Michel
A1  - Wosikowski, Katja
A1  - Itzel, Timo
A1  - Teufel, Andreas
A1  - Schuppan, Detlef
A1  - Stojanovic, Ana
A1  - Cerwenka, Adelheid
A1  - Nittka, Stefanie
A1  - Piiper, Albrecht
A1  - Gaiser, Timo
A1  - Beraza, Naiara
A1  - Milkiewicz, Malgorzata
A1  - Milkiewicz, Piotr
A1  - Brain, John G.
A1  - Jones, David E. J.
A1  - Weiss, Thomas S.
A1  - Zanger, Ulrich M.
A1  - Ebert, Matthias
A1  - Meindl-Beinker, Nadja M.
T1  - TGF-β2 silencing to target biliary-derived liver diseases
T2  - Gut
N2  - Objective: TGF-β2 (TGF-β, transforming growth factor beta), the less-investigated sibling of TGF-β1, is deregulated in rodent and human liver diseases. Former data from bile duct ligated and MDR2 knockout (KO) mouse models for human cholestatic liver disease suggested an involvement of TGF-β2 in biliary-derived liver diseases.
Design: As we also found upregulated TGFB2 in liver tissue of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), we now fathomed the positive prospects of targeting TGF-β2 in early stage biliary liver disease using the MDR2-KO mice. Specifically, the influence of TgfB2 silencing on the fibrotic and inflammatory niche was analysed on molecular, cellular and tissue levels.
Results: TgfB2-induced expression of fibrotic genes in cholangiocytes and hepatic stellate cellswas detected. TgfB2 expression in MDR2-KO mice was blunted using TgfB2-directed antisense oligonucleotides (AON). Upon AON treatment, reduced collagen deposition, hydroxyproline content and αSMA expression as well as induced PparG expression reflected a significant reduction of fibrogenesis without adverse effects on healthy livers. Expression analyses of fibrotic and inflammatory genes revealed AON-specific regulatory effects on Ccl3, Ccl4, Ccl5, Mki67 and Notch3 expression. Further, AON treatment of MDR2-KO mice increased tissue infiltration by F4/80-positive cells including eosinophils, whereas the number of CD45-positive inflammatory cells decreased. In line, TGFB2 and CD45 expression correlated positively in PSC/PBC patients and localised in similar areas of the diseased liver tissue.
Conclusions: Taken together, our data suggest a new mechanistic explanation for amelioration of fibrogenesis by TGF-β2 silencing and provide a direct rationale for TGF-β2-directed drug development.
KW  - TGF-beta
KW  - cholestasis
KW  - fibrosis
KW  - primary biliary cirrhosis
KW  - primary sclerosing cholangitis
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/53137
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-531373
SN  - 1468-3288
SN  - 0017-5749
N1  - This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
VL  - 0
SP  - 1
EP  - 14
PB  - BMJ Publishing Group
CY  - London
ER  -