Tumor Necrosis Factor-α Regulates Transforming Growth Factor-β-dependent Epithelial-Mesenchymal Transition by Promoting Hyaluronan-CD44-Moesin Interaction
Tumor Necrosis Factor-α Regulates Transforming Growth Factor-β-dependent Epithelial-Mesenchymal Transition by Promoting Hyaluronan-CD44-Moesin Interaction
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DOI：
10.1074/jbc.m109.056523
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发表时间：
2010-02-05
影响因子：
4.8
通讯作者：
Saya, Hideyuki
中科院分区：
文献类型：
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作者：
Takahashi, Eri;Nagano, Osamu;Saya, Hideyuki
异常上皮-间质转化（EMT）参与纤维化疾病和癌症侵袭的发展。细胞-细胞外基质相互作用的改变也有助于这些病理状况。然而，EMT和细胞-细胞外基质相互作用之间的功能相互作用仍然知之甚少。我们现在表明，炎症介质肿瘤坏死因子-α（TNF-α）诱导形成纤维化灶的培养视网膜色素上皮细胞通过激活转化生长因子-β（TGF-β）信号的方式依赖于透明质酸-CD 44-膜突蛋白的相互作用。TNF-α通过蛋白激酶C促进CD 44表达和膜突蛋白磷酸化，导致透明质酸和CD 44的细胞周相互作用。透明质酸-CD 44-膜突蛋白复合物的形成导致细胞-细胞解离和通过肌动蛋白重塑增加细胞运动性。此外，发现该复合物与TGF-β受体II和肌动蛋白微结构域的网格蛋白相关，导致TGF-β信号传导的激活。我们建立了TNF-α诱导的小鼠眼纤维化的体内模型，并且这种眼纤维化在CD 44缺失小鼠中减弱。因此，透明质酸的产生及其与CD 44的相互作用在TNF-α诱导的EMT中起重要作用，并且是纤维化疾病的潜在治疗靶点。
Aberrant epithelial-mesenchymal transition (EMT) is involved in development of fibrotic disorders and cancer invasion. Alterations of cell-extracellular matrix interaction also contribute to those pathological conditions. However, the functional interplay between EMT and cell-extracellular matrix interactions remains poorly understood. We now show that the inflammatory mediator tumor necrosis factor-alpha (TNF-alpha) induces the formation of fibrotic foci by cultured retinal pigment epithelial cells through activation of transforming growth factor-beta (TGF-beta) signaling in a manner dependent on hyaluronan-CD44- moesin interaction. TNF-alpha promoted CD44 expression and moesin phosphorylation by protein kinase C, leading to the pericellular interaction of hyaluronan and CD44. Formation of the hyaluronan-CD44-moesin complex resulted in both cell-cell dissociation and increased cellular motility through actin remodeling. Furthermore, this complex was found to be associated with TGF-beta receptor II and clathrin at actin microdomains, leading to activation of TGF-beta signaling. We established an in vivo model of TNF-alpha-induced fibrosis in the mouse eye, and such ocular fibrosis was attenuated in CD44-null mice. The production of hyaluronan and its interaction with CD44, thus, play an essential role in TNF-alpha-inducedEMTand are potential therapeutic targets in fibrotic disorders.