TGF-β1 induced transdifferentiation of rpe cells is mediated by TAK1.
TGF-β1 induced transdifferentiation of rpe cells is mediated by TAK1.
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DOI：
10.1371/journal.pone.0122229
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Pollack A
中科院分区：
文献类型：
--
作者：
Dvashi Z;Goldberg M;Adir O;Shapira M;Pollack A
增生性玻璃体视网膜病变（PVR）是视网膜脱离（RD）后的一种并发症，伴随纤维化组织的形成。在PVR期间参与纤维化组织发展的主要细胞是视网膜色素上皮（RPE）细胞。RPE细胞经历上皮-间充质转化（EMT），这导致复杂的视网膜脱离和视力丧失。转化生长因子-β1（TGF-β1）被认为是RPE细胞EMT的主要参与者，尽管其机制尚未完全了解。本研究旨在确定转化生长因子β激活的激酶1（TEK 1）可能参与RPE细胞的EMT过程。用5 Z-7 oxozeaenol（TAK 1抑制剂）或SB 431542（TGF-β1受体激酶抑制剂）处理ARPE-19细胞，然后用TGF-β1刺激。免疫荧光、划痕试验、真实的时间PCR和胶原收缩试验评估EMT特征。用蛋白质印迹分析检测Smad 2/3和p38的磷酸化。这项研究表明，TGF-β1刺激RPE细胞增加α-SMA表达，细胞迁移和细胞收缩性，所有这些都是EMT特征。值得注意的是，TAK 1抑制剂的加入消除了所有这些过程。此外，我们由此表明，TAK 1不仅调节TGF-β1（p38）的非经典级联的激活，而且调节经典级联，Smad 2/3激活。因此，RPE细胞中TGF-β反应的结果是TAK 1依赖性的。本研究证实了TGF-β1非经典通路中的TAK 1在PVR的EMT过程中起关键作用，为深入研究PVR的发病机制提供了新的思路。阻止RPE细胞中EMT过程的能力可能会降低PVR时发生的纤维化反应的严重程度，从而获得更好的预后并增加RD治疗成功的可能性。
Proliferative vitreoretinopathy (PVR) is an active process that develops as a complication upon retinal detachment (RD), accompanied by formation of fibrotic tissue. The main cells involved in the development of fibrotic tissue during PVR are the retinal pigment epithelial (RPE) cells. The RPE cells undergo epithelial-mesenchymal transition (EMT) which leads to complex retinal detachment and loss of vision. Transforming growth factor-β1 (TGF-β1) is considered as the main player in the EMT of RPE cells, even though the mechanism is not fully understood. This study was performed to determine the possible involvement of transforming growth factor β activated kinase 1 (TAK1) in the EMT process of the RPE cells. ARPE-19 Cells were treated with 5Z-7 oxozeaenol (TAK1 inhibitor) or SB431542 (TGF-β1 receptor kinase inhibitor) followed by TGF-β1 stimulation. Immunofluorescence, scratch assay Real time PCR and collagen contraction assay assessed the EMT features. The phosphorylation of Smad2/3 and p38 was examined using western blots analysis. This study demonstrates that stimulation of RPE cells with TGF-β1 increases α-SMA expression, cell migration and cell contractility, all of which are EMT features. Remarkably, addition of TAK1 inhibitor abolishes all these processes. Furthermore, we show hereby that TAK1 regulates not only the activation of the non-canonical cascade of TGF-β1 (p38), but also the canonical cascade, the Smad2/3 activation. Thus, the outcome of the TGF-β response in RPE cells is TAK1 dependent. This work demonstrated TAK1, a component of the non-canonical pathway of TGF-β1, is a key player in the EMT process, thus provides deep insight into the pathogenesis of PVR. The ability to halt the process of EMT in RPE cells may reduce the severity of the fibrotic response that occurs upon PVR, leading to a better prognosis and increase the probability of success in RD treatment.
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