Z Gastroenterol 2016; 54(12): 1343-1404
DOI: 10.1055/s-0036-1597348
1. Fibrogenesis
Georg Thieme Verlag KG Stuttgart · New York

Anti-fibrotic and anti-inflammatory consequences of TGF-β2 silencing in biliary liver disease

A Dropmann
1   University of Heidelberg, Molecular Hepatology-Alcohol Associated Diseases, Department of Medicine II, Medical Faculty Mannheim,, Mannheim, Germany
,
B Dewidar
1   University of Heidelberg, Molecular Hepatology-Alcohol Associated Diseases, Department of Medicine II, Medical Faculty Mannheim,, Mannheim, Germany
,
T Dediulia
1   University of Heidelberg, Molecular Hepatology-Alcohol Associated Diseases, Department of Medicine II, Medical Faculty Mannheim,, Mannheim, Germany
,
H Korhonen
3   Isarna Therapeutics GmbH, Isarna Therapeutics GmbH, Munich, Germany
,
M Janicot
3   Isarna Therapeutics GmbH, Isarna Therapeutics GmbH, Munich, Germany
,
A Piiper
4   Johann Wolfgang Goethe-Universität, Frankfurt am Main, Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany
,
D Jones
5   Newcastle University, NIHR Applied Immunobiology and Transplant Research Group, Institute of Cellular Medicine, Newcastle, UK
,
J Brain
5   Newcastle University, NIHR Applied Immunobiology and Transplant Research Group, Institute of Cellular Medicine, Newcastle, UK
,
T Gaiser
6   University of Heidelberg, Mannheim, Germany, Institute of Pathology, University Medical Center Mannheim, Mannheim, Germany
,
TS Weiss
7   Universität Regensburg, Fakultät für Medizin,Klinik und Poliklinik für Kinder- und Jugendmedizin, Experimentelle Pädiatrie, Regensburg, Germany
,
M Ebert
8   University of Heidelberg, Department of Medicine II, Medical Faculty Mannheim, Mannheim, Germany
,
S Dooley
1   University of Heidelberg, Molecular Hepatology-Alcohol Associated Diseases, Department of Medicine II, Medical Faculty Mannheim,, Mannheim, Germany
,
NM Meindl-Beinker
1   University of Heidelberg, Molecular Hepatology-Alcohol Associated Diseases, Department of Medicine II, Medical Faculty Mannheim,, Mannheim, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
19 December 2016 (online)

Also available at
 

Aim: We targeted TGF-β2 expression using antisense oligonucleotides (AONs) in MDR2-KO mice to attenuate fibrogenesis and translated our findings to human PBC and PSC patients.

Methods: In 16 weeks old MDR2-KO mice, TGF-β2 expression was targeted using AONs for 4 weeks. Therapeutic efficacy was evaluated by cell-type specific immunofluorescent analysis of AON biodistribution, tissue morphology, and liver parameters. Expression of TGF-β2 and markers for fibrosis and inflammation were investigated by RT-PCR, immunoblot and immunohistochemistry (IHC). TgfB2 mRNA and TGF-β2 expression were determined in livers and serum of PSC and PBC patients using RT-PCR, IHC and ELISA and correlated to clinicopathological parameters.

Results: In MDR2-KO tissue, TGF-β2 was expressed in fibroblasts and areas of proliferating bile ducts; whereby the AONs accumulated in non-parenchymal cells. While ALT, AST and body weight were not affected, TgfB2 levels, hydroxyproline content, collagen deposition and αSMA protein expression were downregulated in mouse livers upon AON treatment. In line with an induction of PparG, inflammatory infiltrates were significantly reduced. According to MDR2-KO mice, TGFβ2 expression was upregulated in PSC and PBC patients compared to normal livers. Especially PBC patients (GSE79850) classified with high risk (no treatment response, liver transplantation requirement) showed increased TGFB2 expression. Preliminary results indicate that in PBC and PSC, TGF-β2 is also localized in areas of proliferation bile ducts. TGF-β2 protein expression in corresponding sera is currently investigated.

Conclusions: TGF-β2-directed AON application attenuated fibrogenesis and inflammation in MDR2-KO mice. Corresponding upregulation of TGF-β2 in PSC and PBC patients unveils TGF-β2 as an interesting target for treatment of human biliary diseases.