The aryl hydrocarbon receptor and glucocorticoid receptor interact to activate human metallothionein 2A

Sato, Shoko; Shirakawa, Hitoshi; Tomita, Shuhei; Tohkin, Masahiro; Gonzalez, Frank J.; Komai, Michio

doi:10.1016/j.taap.2013.08.017

Cited by 40 publications

(25 citation statements)

References 40 publications

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“…That said, a single metallothionein protein can bind up to 13 copper atoms; thus a small increase in metallothionein could account for a major increase in copper content. Previous studies have connected the induction of metallothionein and the AhR via the glucocorticoid receptor and that is likely occurring here (Sato et al 2013). Other copper chaperones were investigated but none showed any significant change.…”

Section: Discussionmentioning

confidence: 75%

Progression of micronutrient alteration and hepatotoxicity following acute PCB126 exposure

et al. 2015

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Polychlorinated Biphenyls (PCBs) are industrial chemicals that have become a persistent threat to human health due to ongoing exposure. A subset of PCBs, known as dioxin-like PCBs, pose a special threat given their potent hepatic effects. Micronutrients, especially Cu, Zn and Se, homeostatic dysfunction is commonly seen after exposure to dioxin-like PCBs. This study investigates whether micronutrient alteration is the byproduct of the ongoing hepatotoxicity, marked by lipid accumulation, or a concurrent, yet independent event of hepatic damage. A time course study was carried out using male Sprague-Dawley rats with treatments of PCB126, the prototypical dioxin-like PCB, resulting in 6 different time points. Animals were fed a purified diet, based on AIN-93G, for three weeks to ensure micronutrient equilibration. A single IP injection of either tocopherol-stripped soy oil vehicle (5 mL/kg) or 5 umol/kg PCB126 dose in vehicle was given at various time points resulting in exposures of 9 hr, 18 hr, 36 hr, 3 days, 6 days, and 12 days. Mild hepatic vacuolar change was seen as early as 36 hours with drastic changes at the later time points, 6 and 12 days. Micronutrient alterations, specifically Cu, Zn, and Se, were not seen until after day 3 and only observed in the liver. No alterations were seen in the duodenum, suggesting that absorption and excretion may not be involved. Micronutrient alterations occur with ROS formation, lipid accumulation, and hepatomegaly. To probe the mechanistic underpinnings, alteration of gene expression of several copper chaperones was investigated; only metallothionein appeared elevated. These data suggest that the disruption in micronutrient status is a result of the hepatic injury elicited by PCB126 and is mediated in part by metallothionein.

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Section: Discussionmentioning

confidence: 75%

Progression of micronutrient alteration and hepatotoxicity following acute PCB126 exposure

et al. 2015

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“…Metallothionein 2A ( MT2A ), a metal binding enzyme, plays a role in anti-oxidant, anti-apoptosis, detoxification and anti-inflammation [59]. It is also a GR-inducible gene in hepatic cells [60]. We found that MT2A is one of the most up-regulated genes in DEG#3 (Table 3), suggesting MT2A may be one of the factors that mediates GC responsiveness.…”

Section: Discussionmentioning

confidence: 94%

A Comparison of Gene Expression Profiles between Glucocorticoid Responder and Non-Responder Bovine Trabecular Meshwork Cells Using RNA Sequencing

et al. 2017

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The most common ocular side effect of glucocorticoid (GC) therapy is GC-induced ocular hypertension (OHT) and GC-induced glaucoma (GIG). GC-induced OHT occurs in about 40% of the general population, while the other 60% are resistant. This study aims to determine the genes and pathways involved in differential GC responsiveness in the trabecular meshwork (TM). Using paired bovine eyes, one eye was perfusion-cultured with 100nM dexamethasone (DEX), while the fellow eye was used to establish a bovine TM (BTM) cell strain. Based on maximum IOP change in the perfused eye, the BTM cell strain was identified as a DEX-responder or non-responder strain. Three responder and three non-responder BTM cell strains were cultured, treated with 0.1% ethanol or 100nM DEX for 7 days. RNA and proteins were extracted for RNA sequencing (RNAseq), qPCR, and Western immunoblotting (WB), respectively. Data were analyzed using the human and bovine genome databases as well as Tophat2 software. Genes were grouped and compared using Student’s t-test. We found that DEX induced fibronectin expression in responder BTM cells but not in non-responder cells using WB. RNAseq showed between 93 and 606 differentially expressed genes in different expression groups between responder and non-responder BTM cells. The data generated by RNAseq were validated using qPCR. Pathway analyses showed 35 pathways associated with differentially expressed genes. These genes and pathways may play important roles in GC-induced OHT and will help us to better understand differential ocular responsiveness to GCs.

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“…Dexamethasone (DEX), a potent GR agonist, and 3-methylcholanthrene, an AHR agonist, synergistically activate methallothionein 2A in Hep2G hepatocytes [47]. STAT3 and the GR also interact with each other synergistically or antagonistically in a promoter-dependent manner.…”

Section: Anti-inflammatory Mechanisms Of Glucocorticoidsmentioning

confidence: 99%

A gradient of glucocorticoid sensitivity among helper T cell cytokines

Banuelos

2016

Cytokine & Growth Factor Reviews

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Helper T (Th) cells secret specific cytokines that promote immune responses whereas glucocorticoids limit the extent of immune responses by inhibiting cytokine secretion and other functions of Th cells. However, glucocorticoid resistance develops in subgroups of patients with Th cell-driven diseases such as asthma and Crohn’s disease. Recent evidence supports that Th1, Th2, and Th17 cells have distinct glucocorticoid sensitivity. Th1 cells are sensitive to glucocorticoid-induced apoptosis and cytokine suppression while Th2 cells are sensitive to the latter but not the former and Th17 cells are resistant to both. This gradient of glucocorticoid sensitivity of Th cells corresponds to the glucocorticoid sensitivity of the diseases they underlie. We identify the mechanisms contributing to distinct glucocorticoid sensitivity of Th cells and their cytokines in the literature, as this information is useful to improve treatment strategies for glucocorticoid resistant immunological disorders.

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The aryl hydrocarbon receptor and glucocorticoid receptor interact to activate human metallothionein 2A

Cited by 40 publications

References 40 publications

Progression of micronutrient alteration and hepatotoxicity following acute PCB126 exposure

Progression of micronutrient alteration and hepatotoxicity following acute PCB126 exposure

A Comparison of Gene Expression Profiles between Glucocorticoid Responder and Non-Responder Bovine Trabecular Meshwork Cells Using RNA Sequencing

A gradient of glucocorticoid sensitivity among helper T cell cytokines

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