Secondly as pointed out by Sulentic and Kaminski

Secondly, as pointed out by Sulentic and Kaminski in their recent paper [90], most of the AhR literature to date has focused on mouse AhR. Although both mouse and human AhR are interchangeable in many in vitro systems, the in vivo ligand binding affinity is drastically different between the two AhRs, with the mouse apexbio dilution sale showing ∼10-fold higher binding affinity to TCDD than that of human AhR [115]. Thus, many effects seen in mouse models remain to be confirmed in human cells. Given the increasingly important role of AhR in immunomodulation, there is no doubt that advancement in this area would have significant impact on our understanding of the physiological functions of AhR in the human body. Finally, a limited number of genetic variations in the human AhR locus have been reported, although most of these polymorphisms do not show obvious differences in simple reporter gene assays [116]. In 2008, the international 1000 genomes project (http://www.1000genomes.org/) was launched with the aim of sequencing 2500 individuals from all ethnic populations to identify the majority of genetic variants that have frequencies of at least 1% in the populations [117]. At this stage, there are more than 100 SNPs (single nucleotide polymorphisms) documented for human AhR cDNA alone, including 30 synonymous and nonsynonymous SNPs in the coding region and 75 SNPs in the untranslated region. Extending the search to include the entire AhR locus identified hundreds of SNPs. There is no doubt that with the timely completion of this project in the near future, more of AhR polymorphisms will be revealed. It will thus be interesting to study effects of these AhR polymorphisms not only on xenobiotic metabolism, but also in the context of immune disorders now that many distinct functions of AhR in immunity have become apparent.
Conflict of interest statement
Acknowledgements We apologize to all those researchers whose work could not be cited and for not comment on all of the relevant studies due to space limitation. This work was supported by the Australian Research Council.
Introduction AHR is a ligand-dependent transcription factor, best known for mediating the biotransformation and carcinogenic/teratogenic effects of environmental toxins [e.g., 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD), a prototypical xenobiotic ligand for AHR]. The Ahr gene was cloned in the early 1990s [1–4], and much of our understanding of AHR function initially came from studies in toxicology and pharmacology, which focused on its role in response to xenobiotics [5]. The perspective on AHR changed when it was revealed to be an important regulator of the development and function of both innate and adaptive immune cells, and that this role was mediated by the ability of AHR to respond to endogenous ligands generated from the host cell, diet, and from microbiota [6–8]. AHR is currently considered to function as an environmental sensor, connecting ‘outside’ environmental signals to ‘inside’ cellular processes, with important consequences for immune cell function (Figure 1). Recent findings have provided new insights into the role of AHR in different settings, revealing complex regulatory pathways that guide tissue and context-specific functions for AHR in both homeostasis and during an immune response [9–11]. This article reviews these findings and integrates them into current understanding of the mechanisms that regulate AHR transcription and function, and the physiological and pathological roles of AHR upon activation by endogenous ligands. I propose a conceptual framework in which AHR function is determined by three factors: the amount of AHR in any given cell, the abundance and potency of AHR ligands within a particular tissue, and the tissue microenvironment wherein AHR+ cells reside. <br> AHR Structure and Function AHR is a ligand-dependent nuclear receptor and belongs to the basic helix-loop-helix (bHLH)/Per–Arnt–Sim (PAS) family of proteins (Figure 2) [12]. In the absence of a ligand, AHR is retained in the cytosol and complexes with the chaperone proteins, HSP90 (heat-shock protein 90kDa), AIP (aryl hydrocarbon receptor interacting protein, also known as XAP2 or ARA9), and p23 (also known as PTGES3). Ligand binding results in a conformational change that in turn leads to its nuclear translocation. Release of AHR from its chaperones requires the dimerization of AHR with another bHLH/PAS-domain transcription factor – the AHR nuclear translocator (ARNT) (also known as hypoxia-inducible factor 1β, HIF1β), which has constitutive nuclear localization. The AHR–ARNT complex binds to the cognate DNA motifs referred to as AHR-responsive elements (AhRE), dioxin response elements (DRE), or xenobiotic response elements (XRE), to initiate transcription of the target genes or regulate gene transcription (Figure 2B). It is unclear whether dimerization with ARNT is absolutely required for AHR transcriptional activity, or whether AHR can regulate transcription by interacting with factors other than ARNT. ARNT can dimerize with HIF1α [13], and thus ARNT likely has gene targets (and associated functions) that are independent of AHR. Direct comparison of the role of AHR and ARNT in different cell types using conditional loss-of-function approaches may shed light on these questions.