Dexamethasone accelerates degradation of aryl hydrocarbon receptor (AHR) and suppresses CYP1A1 induction in placental JEG-3 cell line

Stejskalová, Lucie; Rulcova, Alice; Vrzal, Radim; Dvořák, Zdeněk; Pávek, Petr

doi:10.1016/j.toxlet.2013.09.014

Cited by 17 publications

(9 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, tapinarof-induced upregulation of the mRNA level of CYP1A1, a typical AHR-responsive gene, was found to be partially inhibited by dexamethasone (Supplementary Figure S5A). These findings suggest that glucocorticoid treatment interferes with AHR activation induced by tapinarof treatment, which is consistent with reports describing that dexamethasone suppresses AHR agonist-mediated CYP1A1 upregulation in human ovarian granulosa [41] and choriocarcinoma cell lines [42]. We also found that baricitinib or JTE-052 did not interfere with the upregulation of CYP1A1 mRNA expression induced by tapinarof treatment (Supplementary Figure S5E,F), confirming that they did not act directly on AHR activation.…”

Section: Cell Culturesupporting

confidence: 92%

IL-24 Negatively Regulates Keratinocyte Differentiation Induced by Tapinarof, an Aryl Hydrocarbon Receptor Modulator: Implication in the Treatment of Atopic Dermatitis

Hashimoto-Hachiya

Takao

et al. 2020

IJMS

View full text Add to dashboard Cite

Skin barrier dysfunction, including reduced filaggrin (FLG) and loricrin (LOR) expression, plays a critical role in atopic dermatitis (AD) development. Since aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, mediates keratinocyte differentiation, it is a potential target for AD treatment. Recently, clinical studies have shown that tapinarof, an AHR modulator, attenuated the development of AD. To examine the molecular mechanism involved in this, we analyzed tapinarof-treated normal human epidermal keratinocytes (NHEKs). Tapinarof upregulated FLG and LOR mRNA and protein expression in an AHR-dependent manner. Tapinarof also induced the secretion of IL-24, a cytokine that activates Janus kinase (JAK)-signal transducer and activator of transcription (STAT), leading to the downregulation of FLG and LOR expression. Knockdown of either IL-24 or STAT3 expression by small interfering RNA (siRNA) transfection augmented the upregulation of FLG and LOR expression induced by tapinarof, suggesting that inhibition of the IL-24/STAT3 axis during AHR activation supports the improvement of skin barrier dysfunction. Furthermore, tapinarof alone could restore the downregulation of FLG and LOR expression induced by IL-4, a key cytokine of AD, and its combination with JAK inhibitors enhanced this effect. These findings provide a new strategy for treating AD using AHR modulators and JAK inhibitors.

show abstract

Section: Cell Culturesupporting

confidence: 92%

IL-24 Negatively Regulates Keratinocyte Differentiation Induced by Tapinarof, an Aryl Hydrocarbon Receptor Modulator: Implication in the Treatment of Atopic Dermatitis

Hashimoto-Hachiya

Takao

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…While cotreated with TCDD + Dex, AHR translocation was significantly decreased. In contrast, GR translocation was also significantly reduced by TCDD + Dex, consistent with a previous report that Dex downregulated AHR protein level by AHR degradation in the presence of AHR ligand in JEG-3 cells [28]. Our results suggest that the reduction of AHR nuclear translocation by Dex treatment might be a critical mechanism of inhibition of AHR target gene expression by Dex treatment.…”

Section: Resultssupporting

confidence: 92%

Crosstalk between Aryl Hydrocarbon Receptor and Glucocorticoid Receptor in Human Retinal Pigment Epithelial Cells

Jin

Choi

Jeong

2017

International Journal of Endocrinology

View full text Add to dashboard Cite

The aryl hydrocarbon receptor (AHR) is known to mediate the cellular reaction involved in processing environmental contaminants and, ultimately, preventing accumulation of unfavorable extra lipids and proteins. Glucocorticoid receptor (GR) mediates the expression of genes associated with anti-inflammatory properties. Because AHR and GR are closely related in lipid metabolic dysregulation and inflammation, we speculate that AHR and GR may play a crucial role in AMD pathogenesis and focus on their crosstalk in human retinal pigment epithelial cells (ARPE-19). However, how AHR and GR regulate each other's signaling pathways is still poorly understood. In this research, we demonstrate that GR attenuates AHR-mediated gene expression by inhibition of nuclear translocation of AHR mediated by TCDD. Chromatin immunoprecipitation analysis demonstrated that GR repress AHR recruitment and chromatin accessibility response to TCDD + Dex treatment leading to repression of AHR target genes. In contrast, AHR facilitates GR-mediated expression in ARPE-19. AHR increases GR recruitment on GRE of GR target genes. Coimmunoprecipitation assay revealed that AHR is associated with GR in ARPE-19 cells and the interaction is enhanced by the addition of TCDD and Dex. Taken together, these studies provide a molecular mechanism of crosstalk between AHR and GR in target gene expression in ARPE-19 cells.

show abstract

“…In the study by Davarinos and Pollenz [18], treatment of rat smooth muscle cells with MG132 had no effect on AhR protein unless cotreated with TCDD, which prevented AhR degradation. Interestingly, we recently observed a decrease in AhR protein in JEG-3 choriocarcinoma cell line treated with MG132 or bortezomib [45], consistently with our observation in hepatocytes (Figure 3c). Surprisingly, the PXR protein level was affected quite differently by MG132 or bortezomib.…”

Section: Discussionsupporting

confidence: 91%

The comparative effects of diethyldithiocarbamate–copper complex with established proteasome inhibitors on expression levels of CYP1A2/3A4 and their master regulators, aryl hydrocarbon and pregnane X receptor in primary cultures of human hepatocytes

Vrzal

Dvořák

2016

Fundamemntal Clinical Pharma

Self Cite

View full text Add to dashboard Cite

In the recent years, a therapeutic potential of disulfiram (Antabuse) complex with copper, as an anticancer drug, was recognized towards several cancer cell lines. The proteasome was suggested as one of the cellular targets for this compound. As the therapeutic use of diethyldithiocarbamate-copper complex (CuET) is expected to increase, it is of great interest to know whether this compound may be the source of drug-drug interactions via the induction of biotransformation enzymes, especially cytochromes P450 (CYPs). To this purpose, we examined the effect of CuET and compared it with typical inducers (rifampicin and dioxin) of CYPs and with well-established proteasome inhibitors (MG132 and bortezomib). Diethyldithiocarbamate-copper complex revealed inconsistent and rather modulatory effect on the expression of CYP1A2 and CYP3A4 in several cultures of human hepatocytes. Moreover, it was able to cause neither ubiquitin accumulation nor significant and dose-dependent inhibition of proteasome activity. It had no effect on essential transcription factors involved in regulation of selected CYPs, aryl hydrocarbon (AhR) nor pregnane X receptor (PXR). However, the AhR protein was increased in majority of examined hepatocyte cultures. The main finding of this study is that: (i) disulfiram-copper complex is not the cause of drug-drug interactions via CYP1A2/3A4 induction; (ii) proteasome inhibitors may have different impact on studied parameters in given in vitro system.

show abstract

Dexamethasone accelerates degradation of aryl hydrocarbon receptor (AHR) and suppresses CYP1A1 induction in placental JEG-3 cell line

Cited by 17 publications

References 37 publications

IL-24 Negatively Regulates Keratinocyte Differentiation Induced by Tapinarof, an Aryl Hydrocarbon Receptor Modulator: Implication in the Treatment of Atopic Dermatitis

IL-24 Negatively Regulates Keratinocyte Differentiation Induced by Tapinarof, an Aryl Hydrocarbon Receptor Modulator: Implication in the Treatment of Atopic Dermatitis

Crosstalk between Aryl Hydrocarbon Receptor and Glucocorticoid Receptor in Human Retinal Pigment Epithelial Cells

The comparative effects of diethyldithiocarbamate–copper complex with established proteasome inhibitors on expression levels of CYP1A2/3A4 and their master regulators, aryl hydrocarbon and pregnane X receptor in primary cultures of human hepatocytes

Contact Info

Product

Resources

About