Notch1 Signaling in FIZZ1 Induction of Myofibroblast Differentiation
Notch1 Signaling in FIZZ1 Induction of Myofibroblast Differentiation
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DOI：
10.2353/ajpath.2009.080618
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发表时间：
2009-05-01
影响因子：
6
通讯作者：
Phan, Sem H.
中科院分区：
文献类型：
--
作者：
Liu, Tianju;Hu, Biao;Phan, Sem H.
Notch1 是一种进化上保守的受体，可调节细胞命运，包括分化、增殖和凋亡等事件。肌成纤维细胞分化是肺纤维化的一个关键特征。存在于炎症区 1 (FIZZ1) 中，由于其能够诱导肌成纤维细胞分化，因此具有直接纤维化特性。然而，介导 FIZZ1 诱导肌成纤维细胞分化的下游信号通路仍然未知。本研究的目的是探讨Notch信号在FIZZ1诱导肺肌成纤维细胞分化中的作用，从而探讨Notch1在肺纤维化中的潜在作用。结果表明，FIZZ1 增加了 Notch1 (NIC) 及其配体 Jagged1 及其靶基因 Hes1 的激活胞内结构域的表达水平。这与α-平滑肌肌动蛋白表达水平升高有关。成纤维细胞α-平滑肌肌动蛋白的表达由NIC的过度表达诱导，但由于NIC的抑制而受到抑制。此外，从缺乏 GDP-4-keto-6-deoxymamiose3,5-epimerase-4-reductase 酶（FX 敲除）的小鼠中分离出的肺成纤维细胞对 FIZZ1 的反应性显着降低，而补充岩藻糖可逆转这种情况。在缺乏外源岩藻糖的情况下，这些 FX 缺陷细胞表现出岩藻糖基化缺陷，而岩藻糖基化是 Notch 信号传导所必需的。这些基因敲除小鼠还表现出肺纤维化受损。这些发现表明，响应 FIZZ1 的 Notch1 信号传导可能在肺纤维化期间的肌成纤维细胞分化中发挥重要作用。 （Am J Pathol 2009，174：1745-1755；DOI：10.2353/ajpath.2009.080618）
Notch1 is an evolutionarily conserved receptor that regulates cell fate, including such events as differentiation, proliferation, and apoptosis. Myofibroblast differentiation is a key feature of lung fibrosis. Found in inflammatory zone 1 (FIZZ1) has direct fibrogenic properties because of its ability to induce myofibroblast differentiation. However, the downstream signaling pathway that mediates FIZZ1 induction of myofibroblast differentiation remains unknown. The objective of this study was to investigate the involvement of Notch signaling in FIZZ1 induction of lung myofibroblast differentiation and thus explore the potential role of Notch1 in pulmonary fibrosis. The results showed that FIZZ1 increased the expression levels of activated intracellular domain of Notch1 (NIC), its ligand Jagged1, and its target gene Hes1. which were associated with elevated a-smooth muscle actin expression levels. Fibroblast a-smooth muscle actin expression is induced by the overexpression of NIC but is suppressed by the inhibition of NIC. Moreover, lung fibroblasts that were isolated from mice lacking the GDP-4-keto-6-deoxymamiose3,5-epimerase-4-reductase enzyme (FX knockout) exhibited significantly reduced responsiveness to FIZZ1, which was reversed by fucose supplementation. In the absence of exogenous fucose, these FX-deficient cells exhibited defective fucosylation, which is required for Notch signaling. These knockout mice also showed impaired lung fibrosis. These findings suggest that Notch1 signaling in response to FIZZ1 may play a significant role in myofibroblast differentiation during lung fibrosis. (Am J Pathol 2009, 174:1745-1755; DOI: 10.2353/ajpath.2009.080618)