TGF-β2 silencing to target biliary-derived liver diseases
- 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.
Author: | Anne Dropmann, Steven DooleyORCiDGND, Bedair Dewidar, Seddik Hammad, Tatjana Dediulia, Julia Werle, Vanessa Hartwig, Shahrouz Ghafoory, Stefan WölflORCiDGND, Hanna Korhonen, Michel Janicot, Katja Wosikowski, Timo Itzel, Andreas TeufelORCiDGND, Detlef SchuppanORCiDGND, Ana Stojanovic, Adelheid CerwenkaORCiDGND, Stefanie Nittka, Albrecht PiiperORCiD, Timo GaiserORCiDGND, Naiara Beraza, Malgorzata Milkiewicz, Piotr Milkiewicz, John G. Brain, David E. J. Jones, Thomas S. WeißORCiD, Ulrich M. Zanger, Matthias Ebert, Nadja M. Meindl-BeinkerORCiDGND |
---|---|
URN: | urn:nbn:de:hebis:30:3-531373 |
DOI: | https://doi.org/10.1136/gutjnl-2019-319091 |
ISSN: | 1468-3288 |
ISSN: | 0017-5749 |
Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/31992593 |
Parent Title (English): | Gut |
Publisher: | BMJ Publishing Group |
Place of publication: | London |
Document Type: | Article |
Language: | English |
Year of Completion: | 2020 |
Date of first Publication: | 2020/01/28 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2020/03/18 |
Tag: | TGF-beta; cholestasis; fibrosis; primary biliary cirrhosis; primary sclerosing cholangitis |
Volume: | 0 |
Page Number: | 14 |
First Page: | 1 |
Last Page: | 14 |
Note: | 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/. |
HeBIS-PPN: | 463905253 |
Institutes: | Medizin / Medizin |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Sammlungen: | Universitätspublikationen |
Licence (English): | ![]() |