Aryl Hydrocarbon Receptor Activation by TCDD Modulates Expression of Extracellular Matrix Remodeling Genes during Experimental Liver Fibrosis

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.

Differential Effects of Drinking Water Quality on Phagocyte Responses of Broiler Chickens Against Fungal and Bacterial Challenges

“…cytokine TGF-β was also upregulated early in the acute inflammatory response among leukocytes derived from the raw well water group. This is consistent with molecular changes observed in other models with individual chemicals, where exposure was shown to promote higher expression in genes including IL-1β, TGF β, and others (50,54,55). Together, this suggests dysregulation of the acute inflammatory response following exposure to xenobiotics in drinking water.…”

Aryl hydrocarbon receptor and liver fibrosis

“…TCDD can activate HSCs both in vitro and in vivo with an over-expression of pro-fibrotic genes or pro-ECM-remodeling genes (matrix metalloproteinases, procollagens); however since the period of exposure was too short and despite the induction of pro-fibrotic markers, the authors did not observe a liver fibrosis [31,37]. Interestingly, in vitro and in vivo, the effect of TCDD on HSCs might be due to the activation of several signaling pathways (not only the classically-described AhR-ARNT signaling pathway); TCDD-induced proliferation of HSCs was indeed blocked by an inhibitor of the PI3K, but not the production of monocyte chemoattractant protein-1 (MCP-1), which contributes to the development of a local inflammation [29,30].…”

Regulation of in vitro and in vivo Hepatic Stellate Cell Activation by the Ayrl Hydrocarbon Receptor

“…Previous studies have shown that TCDD treatment modulates ECM remodeling genes in vivo (Lamb et al, 2016b). Interestingly, AhR removal had minimal effects on the expression of these two genes, implying that endogenous AhR signaling play a minimal role in regulating gene expression for TGFB1 and COL1A1.…”

“…In fact, chronic administration of CCl4 is a well-established model of experimental liver fibrosis (reviewed in Delire et al, 2015). Our lab recently used this model to show that AhR activation by TCDD increased necroinflammation and HSC activation in the CCl4-injured mouse liver Lamb et al, 2016b).…”