Abstract
The aryl hydrocarbon receptor (AhR) is a soluble, ligand-activated transcription factor that mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Increasing evidence implicates the AhR in regulating extracellular matrix (ECM) homeostasis. We recently reported that TCDD increased necroinflammation and myofibroblast activation during liver injury elicited by carbon tetrachloride (CCl4). However, TCDD did not increase collagen deposition or exacerbate fibrosis in CCl4-treated mice, which raises the possibility that TCDD may enhance ECM turnover. The goal of this study was to determine how TCDD impacts ECM remodeling gene expression in the liver. Male C57BL/6 mice were treated for 8 weeks with 0.5 mL/kg CCl4, and TCDD (20 μg/kg) was administered during the last two weeks. Results indicate that TCDD increased mRNA levels of procollagen types I, III, IV, and VI and the collagen processing molecules HSP47 and lysyl oxidase. TCDD also increased gelatinase activity and mRNA levels of matrix metalloproteinase- (MMP-) 3, MMP-8, MMP-9, and MMP-13. Furthermore, TCDD modulated expression of genes in the plasminogen activator/plasmin system, which regulates MMP activation, and it also increased TIMP1 gene expression. These findings support the notion that AhR activation by TCDD dysregulates ECM remodeling gene expression and may facilitate ECM metabolism despite increased liver injury.
Highlights
The aryl hydrocarbon receptor (AhR) is a soluble protein in the basic helix-loop-helix Per/AhR nuclear translocator protein (ARNT)/Sim family of transcriptional regulators that contribute to developmental processes, adaptation to environmental stress, and xenobiotic metabolism [1,2,3]
To determine how TCDD treatment impacts procollagen synthesis during chronic liver injury, we measured the mRNA levels of genes that encode procollagen type I and III and types IV and VI
TCDD treatment elevated Col4a3 mRNA levels in mice that were not treated with CCl4, but this increase was not observed in mice that received both TCDD and CCl4
Summary
The aryl hydrocarbon receptor (AhR) is a soluble protein in the basic helix-loop-helix Per/ARNT/Sim family of transcriptional regulators that contribute to developmental processes, adaptation to environmental stress, and xenobiotic metabolism [1,2,3]. The AhR/ARNT complex binds to DNA at xenobiotic response elements (XREs) and modulates gene transcription. A growing body of evidence indicates that the AhR interacts with other coregulatory proteins in addition to ARNT and can modulate the expression of genes that do not contain XREs [5], which underscores the increasing complexity of AhR-mediated gene regulation. Such AhR-dependent changes in gene expression are believed to underlie most of the toxic responses to TCDD. In the absence of TCDD, endogenous AhR activation is implicated in regulating the expression of genes important for a number of developmental and physiological processes [6, 7]
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