2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces hepatic stellate cell (HSC) activation and liver fibrosis in C57BL6 mouse via activating Akt and NF-κB signaling pathways
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces hepatic stellate cell (HSC) activation and liver fibrosis in C57BL6 mouse via activating Akt and NF-κB signaling pathways
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2,3,7,8-四氯二苯并-对二恶英 (TCDD) 通过激活 Akt 和 NF-kappa B 信号通路诱导 C57BL6 小鼠肝星状细胞 (HSC) 活化和肝纤维化
DOI：
10.1016/j.toxlet.2017.03.013
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发表时间：
2017-05-05
影响因子：
3.5
通讯作者：
Xu, Guangfei
中科院分区：
文献类型：
--
作者：
Han, Ming;Liu, Xipeng;Xu, Guangfei
2，3，7，8-四氯二苯并对二恶英（TCDD）是一种广泛存在的环境污染物，对人类和啮齿类动物具有严重的毒性作用。一些研究表明，TCDD暴露可能促进肝星状细胞（HSC）的活化和肝损伤。然而，环境污染物促进肝损伤的潜在分子机制仍然知之甚少。本研究采用C57 BL/6 J雄性小鼠腹腔注射TCDD建立TCDD染毒动物模型。天狼星红染色和苏木精-伊红（H&E）染色评价显示，我们发现，TCDD暴露的小鼠表现出广泛的肝结构破坏，包括肝细胞坏死，炎性细胞浸润和纤维化。此外，我们发现，TCDD上调促炎细胞因子肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的表达和分泌在培养的HSC中的剂量依赖性的方式。TCDD对细胞因子分泌的影响很可能是通过蛋白激酶B/Akt和核因子κ B（NF-κ B B）途径介导的，如TCDD显著增加HSC中Akt磷酸化和NF-κ B p65核转位的事实所示。此外，Akt抑制剂LY 294002通过阻断Akt磷酸化和NF-κ B活化而显著减弱TCDD触发的HSC活化。这些结果表明，HSC是敏感的TCDD的细胞毒性作用和慢性TCDD暴露可能有助于肝纤维化通过激活HSC Akt和NF-κ B信号通路。(C)2017爱思唯尔B. V.保留所有权利。
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental pollutant that could induce serious toxic effects in both humans and rodents. Some studies suggested that TCDD exposure may facilitate the activation of hepatic stellate cells (HSCs) and liver injury. However, the underlying molecular mechanism by which environmental pollutants promote liver injury remains poorly understood. In the present study, we established an animal model of TCDD exposure by intraperitoneal injection of TCDD in male C57BL/6J mice. As revealed by Sirius red staining and hematoxylin-eosin (H&E) staining evaluation, we found that TCDD-exposed mice showed extensive disruption of liver architecture, including hepatocellular necrosis, inflammatory cell infiltration, and fibrosis. Furthermore, we showed that TCDD up-regulated the expression and secretion of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in a dose-dependent manner in cultured HSCs. The effects of TCDD on cytokine secretion were very likely mediated by protein kinase B/Akt and Nuclear Factor kappa B (NF-kappa B) pathways, as indicated by the fact that TCDD markedly increased Akt phosphorylation and nuclear translocation of NF-kappa B p65 in HSCs. Furthermore, LY294002, an Akt inhibitor, significantly attenuated TCDD-triggered HSC activation through blocking Akt phosphorylation and NF- kappa B activation. These results indicate that HSCs are susceptible to the cytotoxic effects of TCDD and chronic TCDD exposure may contribute to liver fibrosis by activating HSC Akt and NF-kappa B signaling pathways. (C) 2017 Elsevier B.V. All rights reserved.