Ah receptor and NF-κB interactions: mechanisms and physiological implications
Introduction
The aryl hydrocarbon (Ah) receptor and nuclear factor kappa B (NF-κB) are inducible transcription factors, each governing the expression of distinct sets of genes that are important for normal physiology as well as pathophysiological responses. The Ah receptor plays a pivotal role in mediating detoxification of xenobiotics as well as toxic responses induced by dioxin and related compounds ( reviewed in [1], [2], [3], [4], [5], [6], [7]). NF-κB is a key transcription factor in regulating the immune system and inflammatory responses, combating infections and in the response to cellular stresses such as hypoxia and oxidative stress (reviewed in [8], [9], [10]). Recent evidence shows that the Ah receptor and NF-κB physically interact and functionally modulate each other's activities. We have demonstrated that the Ah receptor associates with the p65 (RelA) subunit of NF-κB in mouse hepatoma cells and that the activation of one pathway can downregulate the other [11], [12]. The Ah receptor and NF-κB association has subsequently been confirmed by other investigators in human breast cells [13]. There have been reports from several laboratories demonstrating functional interactions between the Ah receptor and NF-κB pathways [14], [15], [16], [17], [18], [19], [20]. This review is intended to highlight the interactions between the two pathways and potential biological effects as a result of these interactions, as well as the most salient features of the Ah receptor and NF-κB pathways that are relevant to the “cross-talk”.
Section snippets
Ah receptor-regulated gene expression
The Ah receptor gene was first cloned from mouse liver in the early 1990s [21], [22]. Analysis of the Ah receptor gene revealed that it contained domains that were shared by several other proteins. Among these domains are the basic helix-loop-helix (bHLH) motif and Per-ARNT-Sim (PAS) domains. Per and Sim are Drosophila transcription factors, and ARNT (Ah receptor nuclear translocator) is the dimerization partner for the Ah receptor and is essential for binding of the Ah receptor complex to
NF-κB and its role in gene regulation
NF-κB is a family of several evolutionarily conserved eukaryotic transcription factors sharing a common 300-amino acid Rel homology domain (RHD) [8], [9], [10]. RHD controls enhancer binding, dimerization and interactions with the inhibitory IκB (NF-κB inhibitory protein) proteins. In mammals there are five known NF-κB proteins—NF-κB1 (p50 and its precursor p105), NF-κB2 (p52 and its precursor p100), c-Rel, RelA (p65), and RelB. The NF-κB proteins form dimeric complexes which bind to enhancer
Ah receptor–NF-κB interactions
NF-κB is a pleiotropic transcription factor that participates in many of the physiological responses that are affected by TCDD and polycyclic aromatic hydrocarbons, suggesting that these two pathways functionally interact. Using co-immunoprecipitation/Western blot analysis, we demonstrated that the Ah receptor associated with the RelA (p65) subunit of NF-κB, and this association was independent of ligand [11]. Co-immunoprecipitation experiments were performed with total cell extracts of
Acknowledgements
The authors would like to thank Professor Stephen Safe for his comments on this paper. The work was supported in part by ES09859 (to YT), and ES05022 (to M.A.G.).
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2021, Biomedicine and PharmacotherapyCitation Excerpt :However, it is believed that strongly suggested that a decrease in the CYPs mRNA strongly recommended a transcriptional mechanism affecting several transcriptional factors [77,78]. Nuclear factor Kappa B (NF-kB) and the aryl hydrocarbon receptor are the regulatory transcription factor in the inflammatory and immune response, and they regulate the gene expression of many CYPs in human, rats, and mice [77–80]. For example, pyrrolidine dithiocarbamate is an inhibitor of NF-kB that can the capability to block the inflammatory reduction in CYP1A2 activity [81,82].