WNT-5A regulates TGF-β-related activities in liver fibrosis
WNT-5A regulates TGF-β-related activities in liver fibrosis
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DOI：
10.1152/ajpgi.00160.2016
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发表时间：
2017-03-01
影响因子：
4.5
通讯作者：
Gosens, Reinoud
中科院分区：
文献类型：
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作者：
Beljaars, Leonie;Daliri, Sara;Gosens, Reinoud
WNT-5A 是一种分泌性生长因子，属于 Wingless 相关 MMTV 整合家族的非规范成员。先前的研究指出 WNT-5A 与纤维形成因子 TGF-β 之间存在联系，值得进一步研究 WNT-5A 在肝纤维化中的功能作用。因此，我们研究了小鼠和人纤维化肝脏中WNT-5A的表达，并检查了WNT-5A与各种纤维化相关生长因子、细胞因子和细胞外基质蛋白之间的关系。与健康肝脏相比，纤维化小鼠和人类肝脏中 WNT-5A 基因和蛋白的表达显着增加。对小鼠进行回归或治疗干预会导致肝脏 WNT-5A 水平降低，同时胶原蛋白水平降低。免疫组织化学分析显示纤维化隔膜中的 WNT-5A 染色与结蛋白染色共定位，表明肌成纤维细胞中 WNT-5A 表达。体外研究证实了这种细胞类型中的 WNT-5A 表达，并表明与 PDGF-BB 和促炎细胞因子 IL-1 β 和 TNF-α 相比，TGF-β 显着增强 WNT-5A 表达。此外，TGF-β 还可诱导 WNT 受体 FZD2 和 FZD8 的表达。沉默 WNT-5A 后，与非沉默 siRNA 处理的对照相比，TGF-β 刺激的肌成纤维细胞中 I 型胶原蛋白、波形蛋白和纤连蛋白水平降低。有趣的是，抗纤维化细胞因子 IFN γ 在体外和体内均抑制 WNT-5A。与未治疗的纤维化小鼠相比，IFN-γ治疗的纤维化小鼠的 WNT-5A 表达显着减少。总之，WNT-5A 与纤维化小鼠和人类肝脏中的 I 型胶原蛋白水平相似。肌成纤维细胞中的 WNT-5A 表达由促纤维化因子 TGF-β 诱导，并在 TGF-β 诱导的纤维化基质蛋白调节中发挥重要作用，而其表达在体外和体内治疗后均可逆转。
WNT-5A is a secreted growth factor that belongs to the noncanonical members of the Wingless-related MMTV-integration family. Previous studies pointed to a connection between WNT-5A and the fibrogenic factor TGF-beta warranting further studies into the functional role of WNT-5A in liver fibrosis. Therefore, we studied WNT-5A expressions in mouse and human fibrotic livers and examined the relation between WNT-5A and various fibrosis-associated growth factors, cytokines, and extracellular matrix proteins. WNT-5A gene and protein expressions were significantly increased in fibrotic mouse and human livers compared with healthy livers. Regression or therapeutic intervention in mice resulted in decreased hepatic WNT-5A levels paralleled by lower collagen levels. Immunohistochemical analysis showed WNT-5A staining in fibrotic septa colocalizing with desmin staining indicating WNT-5A expression in myofibroblasts. In vitro studies confirmed WNT-5A expression in this cell type and showed that TGF-beta significantly enhanced WNT-5A expression in contrast to PDGF-BB and proinflammatory cytokines IL-1 beta and TNF-alpha. Additionally, TGF-beta induces the expression of the WNT receptors FZD2 and FZD8. After silencing of WNT-5A, reduced levels of collagen type I, vimentin, and fibronectin in TGF-beta-stimulated myofibroblasts were measured compared with nonsilencing siRNA-treated controls. Interestingly, the antifibrotic cytokine IFN gamma suppressed WNT-5A in vitro and in vivo. IFN gamma-treated fibrotic mice showed significantly less WNT-5A expression compared with untreated fibrotic mice. In conclusion, WNT-5A paralleled collagen I levels in fibrotic mouse and human livers. WNT-5A expression in myofibroblasts is induced by the profibrotic factor TGF-beta and plays an important role in TGF-beta-induced regulation of fibrotic matrix proteins, whereas its expression can be reversed upon treatment, both in vitro and in vivo.