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DOI: 10.1055/s-0036-1597348
Anti-fibrotic and anti-inflammatory consequences of TGF-β2 silencing in biliary liver disease
Publikationsverlauf
Publikationsdatum:
19. Dezember 2016 (online)
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.