{"rowid": 70, "title": "[\"TGF-\\u03b22 silencing to target biliary-derived liver diseases\"]", "DOI": "10.1136/gutjnl-2019-319091", "URL": "http://dx.doi.org/10.1136/gutjnl-2019-319091", "created": "2020-01-28T21:17:00Z", "subject": "[\"Gastroenterology\"]", "references-count": "0", "is-referenced-by-count": "0", "ISSN": "[\"0017-5749\", \"1468-3288\"]", "container-title": "Gut", "abstract": "<jats:sec><jats:title>Objective</jats:title><jats:p>TGF-\u03b22 (TGF-\u03b2, transforming growth factor beta), the less-investigated sibling of TGF-\u03b21, 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-\u03b22 in biliary-derived liver diseases.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>As we also found upregulated <jats:italic>TGFB2</jats:italic> in liver tissue of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), we now fathomed the positive prospects of targeting TGF-\u03b22 in early stage biliary liver disease using the MDR2-KO mice. Specifically, the influence of <jats:italic>TgfB2</jats:italic> silencing on the fibrotic and inflammatory niche was analysed on molecular, cellular and tissue levels.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p><jats:italic>TgfB2</jats:italic>-induced expression of fibrotic genes in cholangiocytes and hepatic stellate cellswas detected. <jats:italic>TgfB2</jats:italic> expression in MDR2-KO mice was blunted using <jats:italic>TgfB2</jats:italic>-directed antisense oligonucleotides (AON). Upon AON treatment, reduced collagen deposition, hydroxyproline content and \u03b1SMA expression as well as induced <jats:italic>PparG</jats:italic> 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 <jats:italic>Ccl3</jats:italic>, <jats:italic>Ccl4</jats:italic>, <jats:italic>Ccl5</jats:italic>, <jats:italic>Mki67</jats:italic> and <jats:italic>Notch3</jats:italic> 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, <jats:italic>TGFB2</jats:italic> and CD45 expression correlated positively in PSC/PBC patients and localised in similar areas of the diseased liver tissue.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Taken together, our data suggest a new mechanistic explanation for amelioration of fibrogenesis by TGF-\u03b22 silencing and provide a direct rationale for TGF-\u03b22-directed drug development.</jats:p></jats:sec>", "author_number": "29", "orcids": "[\"http://orcid.org/0000-0002-4840-6240\", \"http://orcid.org/0000-0001-7953-8927\", \"http://orcid.org/0000-0003-3135-1359\", \"http://orcid.org/0000-0002-6022-073X\", \"http://orcid.org/0000-0003-0336-0581\", \"http://orcid.org/0000-0003-0211-352X\"]", "names": "[\"Anne Dropmann\", \"Steven Dooley\", \"Bedair Dewidar\", \"Seddik Hammad\", \"Tatjana Dediulia\", \"Julia Werle\", \"Vanessa Hartwig\", \"Shahrouz Ghafoory\", \"Stefan Woelfl\", \"Hanna Korhonen\", \"Michel Janicot\", \"Katja Wosikowski\", \"Timo Itzel\", \"Andreas Teufel\", \"Detlef Schuppan\", \"Ana Stojanovic\", \"Adelheid Cerwenka\", \"Stefanie Nittka\", \"Albrecht Piiper\", \"Timo Gaiser\", \"Naiara Beraza\", \"Malgorzata Milkiewicz\", \"Piotr Milkiewicz\", \"John G Brain\", \"David E J Jones\", \"Thomas S Weiss\", \"Ulrich M Zanger\", \"Matthias Ebert\", \"Nadja M Meindl-Beinker\"]", "award_numbers": "[\"non\"]", "funder_names": "[\"Robert Bosch Stiftung\", \"Bundesministerium f\\u00fcr Bildung und Forschung\", \"Deutsche Forschungsgemeinschaft\", \"ESF Baden W\\u00fcrttemberg (www.esf-bw.de) and the Ministerium f\\u00fcr Wissenschaft, Forschung und Kunst, Baden W\\u00fcrttemberg\", \"EU\", \"Isarna Therapeutics GmbH\", \"SPP 1937\"]", "funder_dois": "[\"10.13039/501100001646\", \"10.13039/501100002347\", \"10.13039/501100001659\", [\"\"], [\"\"], [\"\"], [\"\"]]"}