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.

Abstract:

: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-α) 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-κB) pathways, as indicated by the fact that TCDD markedly increased Akt phosphorylation and nuclear translocation of NF-κB p65 in HSCs. Furthermore, LY294002, an Akt inhibitor, significantly attenuated TCDD-triggered HSC activation through blocking Akt phosphorylation and NF-κB 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-κB signaling pathways.

journal_name

Toxicol Lett

journal_title

Toxicology letters

authors

Han M,Liu X,Liu S,Su G,Fan X,Chen J,Yuan Q,Xu G

doi

10.1016/j.toxlet.2017.03.013

subject

Has Abstract

pub_date

2017-05-05 00:00:00

pages

10-19

eissn

0378-4274

issn

1879-3169

pii

S0378-4274(17)30107-8

journal_volume

273

pub_type

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