title: 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.
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong 226001, Jiangsu, PR China; Chuzhou Center for Disease Control and Prevention, Chuzhou, 239499 Anhui, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Han
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong 226001, Jiangsu, PR China; Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Huangpu, 200011 Shanghai, PR China.
authors.forename: Xipeng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong 226001, Jiangsu, PR China.
authors.forename: Suyi
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong 226001, Jiangsu, PR China.
authors.forename: Guanglei
authors.initials: G
authors.lastname: Su
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong 226001, Jiangsu, PR China.
authors.forename: Xikang
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong 226001, Jiangsu, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong 226001, Jiangsu, PR China.
authors.forename: Qianting
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong 226001, Jiangsu, PR China. Electronic address: gfxu001@aliyun.com.
authors.forename: Guangfei
authors.initials: G
authors.lastname: Xu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004785:Environmental Pollutants / Q000633:toxicity*; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004785:Environmental Pollutants; D015850:Interleukin-6; D016328:NF-kappa B; D000072317:Polychlorinated Dibenzodioxins; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; Hepatic stellate cell; Liver fibrosis; NF-κB; TCDD