Induction of galectin-1 by TGF-β1 accelerates fibrosis through enhancing nuclear retention of Smad2
Induction of galectin-1 by TGF-β1 accelerates fibrosis through enhancing nuclear retention of Smad2
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DOI：
10.1016/j.yexcr.2014.06.001
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发表时间：
2014-08-01
影响因子：
3.7
通讯作者：
Song, Jie-Young
中科院分区：
文献类型：
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作者：
Lim, Min Jin;Ahn, Jiyeon;Song, Jie-Young
纤维化是接受放射/化学疗法的癌症患者中最严重的副作用之一，特别是肺、胰腺或肾脏的。基于我们先前的发现，半乳糖凝集素-1（Gal-1）在放射诱导的肺纤维化过程中在肺纤维化区域显著增加，我们在此阐明了Gal-1在纤维化过程中的作用和作用机制。我们的研究结果显示，TGF-β 1处理诱导成纤维细胞系（NIH 3 T3和IMR-90）分化为肌成纤维细胞，这可以通过纤维化标志物平滑肌肌动蛋白-α（α-SMA）、纤连蛋白和胶原蛋白（Col-1）的表达增加来证明。我们还观察到Gal-1的表达水平和核积累的显著和时间依赖性增加。TGF-β 1诱导的Gal-1、a-SMA和Col-1的增加可被PI 3-激酶和p38 MAPK抑制剂降低，但ERK不能。Gal-1基因的shRNA敲除降低了Smad 2的磷酸化和核滞留，阻止了成纤维细胞的分化。Gal-1与Smad 2相互作用并磷酸化Smad 2，这可能加速纤维化过程。此外，在博来霉素（BLM）诱导的小鼠体内肺纤维化模型中证实了Gal-1表达的上调。总之，我们的研究结果表明，Gal-1可能通过维持Smad 2的核定位来促进TGF-β 1诱导的成纤维细胞分化，并且可能是治疗肺纤维化疾病的潜在靶点。(C)2014爱思唯尔公司All rights reserved.
Fibrosis is one of the most serious side effects in cancer patients undergoing radio-/ chemotherapy, especially of the lung, pancreas or kidney. Based on our previous finding that galectin-1 (Gal-1) was significantly increased during radiation-induced lung fibrosis in areas of pulmonary fibrosis, we herein clarified the roles and action mechanisms of Gal-1 during fibrosis. Our results revealed that treatment with TGF-beta 1 induced the differentiation of fibroblast cell lines (NIH3T3 and IMR-90) to myofibroblasts, as evidenced by increased expression of the fibrotic markers smooth muscle actin-alpha (alpha-SMA), fibronectin, and collagen (Col-1). We also observed marked and time-dependent increases in the expression level and nuclear accumulation of Gal-1. The TGF-beta 1-induced increases in Gal-1, a-SMA and Col-1 were decreased by inhibitors of PI3-kinase and p38 MAPK, but not ERK. Gal-1 knockdown using shRNA decreased the phosphorylation and nuclear retention of Smad2, preventing the differentiation of fibroblasts. Gal-1 interacted with Smad2 and phosphorylated Smad2, which may accelerate fibrotic processes. In addition, upregulation of Gal-1 expression was demonstrated in a bleomycin (BLM)-induced mouse model of lung fibrosis in vivo. Together, our results indicate that Gal-1 may promote the TGF-beta 1-induced differentiation of fibroblasts by sustaining nuclear localization of Smad2, and could be a potential target for the treatment of pulmonary fibrotic diseases. (C) 2014 Elsevier Inc. All rights reserved.