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.

中文翻译：

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TGF-β2 沉默靶向胆源性肝病

目的 TGF-β2（TGF-β，转化生长因子 β）是 TGF-β1 的研究较少的同胞，在啮齿动物和人类肝脏疾病中被解除管制。来自胆管结扎和 MDR2 敲除 (KO) 人类胆汁淤积性肝病小鼠模型的先前数据表明，TGF-β2 与胆源性肝病有关。设计 由于我们还在原发性硬化性胆管炎 (PSC) 和原发性胆汁性胆管炎 (PBC) 患者的肝组织中发现了上调的 TGFB2，我们现在了解使用 MDR2-KO 小鼠在早期胆汁性肝病中靶向 TGF-β2 的积极前景. 具体来说，在分子、细胞和组织水平上分析了 TgfB2 沉默对纤维化和炎症生态位的影响。结果在胆管细胞和肝星状细胞中检测到TgfB2诱导的纤维化基因的表达。使用 TgfB2 定向反义寡核苷酸 (AON) 减弱 MDR2-KO 小鼠中的 TgfB2 表达。AON 治疗后，减少的胶原沉积、羟脯氨酸含量和αSMA 表达以及诱导的 PparG 表达反映了纤维化的显着减少，而对健康肝脏没有不利影响。纤维化和炎症基因的表达分析揭示了 AON 对 Ccl3、Ccl4、Ccl5、Mki67 和 Notch3 表达的特异性调节作用。此外，MDR2-KO 小鼠的 AON 治疗增加了 F4/80 阳性细胞（包括嗜酸性粒细胞）的组织浸润，而 CD45 阳性炎症细胞的数量减少。同样，TGFB2 和 CD45 表达在 PSC/PBC 患者中呈正相关，并且位于患病肝组织的相似区域。结论 综合起来，