title: Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases human hepatic stellate cell activation.
abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a halogenated aromatic hydrocarbon that elicits toxicity through the aryl hydrocarbon receptor (AhR). In the liver, gross markers of TCDD toxicity are attributed to AhR activation in parenchymal hepatocytes. However, less is known regarding the consequences of TCDD treatment on non-parenchymal cells in the liver. Hepatic stellate cells (HSCs) are non-parenchymal cells that store vitamin A when quiescent. Upon liver injury, activated HSCs lose this storage ability and instead function in the development and maintenance of inflammation and fibrosis through the production of pro-inflammatory mediators and collagen type I. Reports that TCDD exposure disrupts hepatic retinoid homeostasis and dysregulates extracellular matrix remodeling in the liver led us to speculate that TCDD treatment may disrupt HSC activity. The human HSC line LX-2 was used to test the hypothesis that TCDD treatment directly activates HSCs. Results indicate that exposure to 10nM TCDD almost completely inhibited lipid droplet storage in LX-2 cells cultured with retinol and palmitic acid. TCDD treatment also increased LX-2 cell proliferation, expression of α-smooth muscle actin, and production of monocyte chemoattractant protein-1 (MCP-1), all of which are characteristics of activated HSCs. However, TCDD treatment had no effect on Col1a1 mRNA levels in LX-2 cells stimulated with the potent profibrogenic mediator, transforming growth factor-β. The TCDD-mediated increase in LX-2 cell proliferation, but not MCP-1 production, was abolished when phosphoinositide 3-kinase was inhibited. These results indicate that HSCs are susceptible to direct modulation by TCDD and that TCDD likely increases HSC activation through a multi-faceted mechanism.
authors: Department of Biological Sciences, Boise State University, Boise, ID 83725, United States.
authors: Wendy A
authors: WA
authors: Harvey
authors: Department of Biological Sciences, Boise State University, Boise, ID 83725, United States.
authors: Kimberly
authors: K
authors: Jurgensen
authors: Biomolecular Research Center, Boise State University, Boise, ID 83725, United States.
authors: Xinzhu
authors: X
authors: Pu
authors: Biomolecular Sciences Ph.D. Program, Boise State University, Boise, ID 83725, United States.
authors: Cheri L
authors: CL
authors: Lamb
authors: Biomolecular Research Center, Boise State University, Boise, ID 83725, United States; Biomolecular Sciences Ph.D. Program, Boise State University, Boise, ID 83725, United States; Department of Chemistry and Biochemistry, Boise State University, Boise, ID 83725, United States.
authors: Kenneth A
authors: KA
authors: Cornell
authors: Department of Biological Sciences, Boise State University, Boise, ID 83725, United States.
authors: Reilly J
authors: RJ
authors: Clark
authors: Department of Biological Sciences, Boise State University, Boise, ID 83725, United States.
authors: Carolyn
authors: C
authors: Klocke
authors: Department of Biological Sciences, Boise State University, Boise, ID 83725, United States; Biomolecular Sciences Ph.D. Program, Boise State University, Boise, ID 83725, United States. Electronic address: kristenmitchell@boisestate.edu.
authors: Kristen A
authors: KA
authors: Mitchell
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects* / Q000502:physiology; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000378:metabolism
chemical_list: D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon
keywords: Collagen; Hepatic stellate cell; Liver; MCP-1; TCDD