期刊
INTERNATIONAL IMMUNOPHARMACOLOGY
卷 32, 期 -, 页码 76-86出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.intimp.2016.01.013
关键词
Hepatic fibrosis; TGF-beta 1; Smad2; TRAIL; Apoptosis; XIAP
资金
- Chinese National Natural Science Foundation Project [81100302]
- Intercollegiate Key Projects of Nature Science of Anhui Province [KJ2011A174]
The activation of hepatic stellate cells (HSCs) plays a critical role in the development of liver fibrosis. The induction of apoptosis in activated HSCs during the recovery phase of hepatic fibrosis represents a potential anti-fibrotic therapy. We have previously shown that Smad2 protects against hepatic fibrogenesis; however, the role of Smad2 in the regulation of activated HSC apoptosis remains unknown. We hypothesized that Smad2 regulates the apoptosis of activated HSCs, leading to the resolution of liver fibrosis. To test this hypothesis, the livers of rats were harvested at 0 and 4 weeks after hepatic fibrosis was established by CCl4 injection. Furthermore, TGF-beta 1-activated HSCs were treated with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) following the silencing or overexpression of Smad2. Both the phosphorylation of Smad2 and TRAIL were detected in fibrotic liver tissues. The results of TUNEL and alpha-SMA double-staining showed an increase in the apoptosis of activated HSCs during the spontaneous recovery phase. The knockdown of Smad2 reduced TRAIL-induced apoptosis in TGF-beta 1-activated human LX-2 cells and resulted in an increased expression of alpha-SMA and collagen I (Col. I). In contrast, the overexpression of Smad2 increased TRAIL-induced HSC apoptosis and reduced the expression of alpha-SMA and Col. I. The mechanisms underlying these findings were associated with the Smad2-mediated down-regulation of X-linked inhibitor of apoptosis protein (XIAP), resulting in enhanced caspase-3 activity and apoptosis. In conclusion, Smad2 enhances TRAIL-induced apoptosis in activated HSCs, which facilitates the resolution of hepatic fibrosis. (C) 2016 Elsevier B.V. All rights reserved.
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