Academic journal article Environmental Health Perspectives

Transgenic Overexpression of Aryl Hydrocarbon Receptor Repressor (AhRR) and AhR-Mediated Induction of CYP1A1, Cytokines, and Acute Toxicity

Academic journal article Environmental Health Perspectives

Transgenic Overexpression of Aryl Hydrocarbon Receptor Repressor (AhRR) and AhR-Mediated Induction of CYP1A1, Cytokines, and Acute Toxicity

Article excerpt

Introduction

The function and activity of the aryl hydrocarbon receptor (AhR) is controlled at different levels. In an inactive state the AhR is known to form a complex with heat shock protein (HSP) 90, hepatitis B virus X-associated protein (XAP2) and p23 in the cytosol (Denison and Nagy 2003). Activation of the classical AhR signaling pathway by ligands like 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) leads to nuclear translocation of the AhR forming a heterodimer with the AhR nuclear translocator (ARNT) (Reisz-Porszasz et al. 1994). The AhR/ARNT heterodimer binds to dioxin responsive enhancer (DRE) sequences known to induce Cyp1a1 (cytochrome P450 1a1) and other genes of the AhR gene battery, such as Cyp1a2, Cyp1b1, and NAD(P)H dehydrogenase [quinone] 1 (NQO1) (Okey 2007).

Besides the ligand-dependent activation of AhR, an alternative pathway of AhR signaling has been proposed from studies showing activation and nuclear translocation of the AhR by the second messenger molecule cAMP or forskolin in a protein kinase A- (PKA) dependent manner (Oesch-Bartlomowicz et al. 2005; Vogel et al. 2007b). The ligand-dependent degradation and inactivation of the AhR is processed through the proteasome and other proteases (Davarinos and Pollenz 1999; Morales and Perdew 2007). Another mechanism of AhR control, first reported by Mimura et al. (1999) revealed a new AhR/ ARNT- and DRE-regulated gene, known as the AhR repressor (AhRR). From their results, the authors concluded that the AhRR competes with AhR for dimerization with their common partner ARNT, which would inhibit the downstream DNA-binding to DREs and transcriptional activation of genes regulated by the AhR/ARNT dimer. However, studies addressing the role of ARNT for the inhibitory action of AhRR suggested a more complex mechanism than the hypothesized mechanism of negative feedback through sequestration of ARNT to regulate AhR signaling (Haarmann-Stemmann and Abel 2006; Evans et al. 2008; Hahn et al. 2009). Recently, the AhRR has been shown to act as a tumor suppressor gene in several types of cancer cells (Zudaire et al. 2008), which has attracted the interest of an increasing number of cancer scientists. Epigenetic changes of the AhRR have been reported in epidemiological studies and have been associated with exposure to cigarette smoke (Lee et al. 2015; Novakovic et al. 2014; Gao et al. 2015; Fasanelli et al. 2015). Such tumor suppressing actions of AhRR can no longer be explained by the existing theory alone.

Here, we generated the first strain of AhRR overexpressing transgenic B6 mice (AhRR Tg) to investigate if the AhRR is capable of exclusively suppressing the expression of members of the AhR gene battery induced via the classical AhR/ARNT pathway, such as CYP1A1. Furthermore, the effect of the AhRR on TCDD-induced inflammatory genes like cytokines has not been examined. Several reports, including our own work, show that the induction of cytokines, such as interleukin (IL)-6 or IL-8, involves AhR interacting with non-basic helix-loop-helix (bHLH) proteins, such as RelA and RelB, of the NF-[kappa]B family through the non-canonical AhR signaling pathway (Vogel et al. 2007b; DiNatale et al. 2010). Interestingly, previous studies showed that the AhRR may interact with non-bHLH proteins [e.g. estrogen receptor [alpha] (ER[alpha])] (Kanno et al. 2008).

Although the AhR has an anti-inflammatory role as a mediator of the expression of the immune regulatory enzyme indoleamine 2,3,-dioxygenase (Vogel et al. 2008) and a role in the differentiation of T regulatory cells (Funatake et al. 2005), previous studies have shown that TCDD induces the expression of pro-inflammatory cytokines, such as IL-1[beta], IL-6, or tumor necrosis factor [alpha] (TNF[alpha]) (Sutter et al. 1991; Vogel et al. 1997; Rier et al. 2001; Pohjanvirta et al. 2012). In addition, activation of AhR can lead to altered expression of chemokines, including IL-8, as well as CCL and CXCL chemokines (Vogel et al. …

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