Ah receptor and NF-κB interactions: mechanisms and physiological implications

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Abstract

The aryl hydrocarbon (Ah) receptor mediates most of the toxic effects induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds, which are ubiquitous environmental contaminants causing toxic responses in human and wildlife. Nuclear factor kappa B (NF-κB) is a pleiotropic transcription factor that plays a pivotal role in a wide array of physiological and pathological responses including immune modulation, inflammatory responses and apoptosis. Many physiological functions adversely affected by TCDD are also known to be regulated by NF-κB, such as immune activation, maintenance of skin differentiation, control of cell proliferation and survival, as well as induction of xenobiotic metabolizing enzymes. In the past few years, evidence has emerged to show that the Ah receptor and NF-κB interact and transcriptionally modulate each other. This review discusses Ah receptor–NF-κB interactions and examines potential mechanistic explanations for toxic responses as a result of TCDD exposure and the suppression of cytochrome P450 1A1/1A2 by stress stimuli such as inflammation and infection.

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.).

References (108)

  • Q. Ma et al.

    A novel cytoplasmic protein that interacts with the Ah receptor, contains tetratricopeptide repeat motifs, and augments the transcriptional response to 2,3,7,8-tetrachlorodibenzo-p-dioxin

    J. Biol. Chem.

    (1997)
  • L.A. Carver et al.

    Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo

    J. Biol. Chem.

    (1997)
  • A. Kazlauskas et al.

    Evidence that the co-chaperone p23 regulates ligand responsiveness of the dioxin (aryl hydrocarbon) receptor

    J. Biol. Chem.

    (1999)
  • H.I. Swanson et al.

    DNA binding specificities and pairing rules of the Ah receptor, ARNT, and SIM proteins

    J. Biol. Chem.

    (1995)
  • M.S. Denison et al.

    The DNA recognition site for the dioxin-Ah receptor complex. Nucleotide sequence and functional analysis

    J. Biol. Chem.

    (1988)
  • L. Zhang et al.

    Characterization of the mouse CYP1B1 gene. Identification of an enhancer region that directs aryl hydrocarbon receptor-mediated constitutive and induced expression

    J. Biol. Chem.

    (1998)
  • L.V. Favreau et al.

    Transcriptional regulation of the rat NAD(P)H: quinone reductase gene. Identification of regulatory elements controlling basal level expression and inducible expression by planar aromatic compounds and phenolic antioxidants

    J. Biol. Chem.

    (1991)
  • W.K. Chan et al.

    Cross talk between the aryl hydrocarbon receptor and hypoxia inducible factor signaling pathways. Demonstration of competition and compensation

    J. Biol. Chem.

    (1999)
  • N.A. Davarinos et al.

    Aryl hydrocarbon receptor imported into the nucleus following ligand binding is rapidly degraded via the cytoplasmic proteasome following nuclear export

    J. Biol. Chem.

    (1999)
  • E. Enan et al.

    Identification of c-Src as the integral component of the cytosolic Ah receptor complex, transducing the signal of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) through the protein phosphorylation pathway

    Biochem. Pharmacol.

    (1996)
  • H. Zhong et al.

    The transcriptional activity of NF-kappa B is regulated by the I kappa B-associated PKAc subunit through a cyclic AMP-independent mechanism

    Cell

    (1997)
  • H. Zhong et al.

    Phosphorylation of NF-kappa B p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300

    Mol. Cell

    (1998)
  • D. Wang et al.

    Tumor necrosis factor alpha-induced phosphorylation of RelA/p65 on Ser529 is controlled by casein kinase II

    J. Biol. Chem.

    (2000)
  • Z. Wang et al.

    Interleukin-1 beta and dexamethasone regulate gene expression of prostaglandin H synthase-2 via the NF-κB pathway in human amnion derived WISH cells

    Prostaglandins Leukot. Essent. Fatty Acids

    (1998)
  • C. Vogel et al.

    Modulation of prostaglandin H synthase-2 mRNA expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice

    Arch. Biochem. Biophys.

    (1998)
  • M.B. Kumar et al.

    Differential recruitment of coactivator RIP140 by Ah and estrogen receptors. Absence of a role for LXXLL motifs

    J. Biol. Chem.

    (1999)
  • K.A. Sheppard et al.

    Nuclear integration of glucocorticoid receptor and nuclear factor-kappa B signaling by CREB-binding protein and steroid receptor coactivator-1

    J. Biol. Chem.

    (1998)
  • Y. Kamei et al.

    A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors

    Cell

    (1996)
  • S.K. Lee et al.

    Silencing mediator of retinoic acid and thyroid hormone receptors, as a novel transcriptional corepressor molecule of activating protein-1, nuclear factor-kappa B, and serum response factor

    J. Biol. Chem.

    (2000)
  • T.A. Nguyen et al.

    Interactions of nuclear receptor coactivator/corepressor proteins with the aryl hydrocarbon receptor complex

    Arch. Biochem. Biophys.

    (1999)
  • D.J. Waxman

    P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR

    Arch. Biochem. Biophys.

    (1999)
  • R. Barouki et al.

    Repression of cytochrome P450 1A1 gene expression by oxidative stress: mechanisms and biological implications

    Biochem. Pharmacol.

    (2001)
  • G.R. Burleson et al.

    Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on influenza virus host resistance in mice

    Fundam. Appl. Toxicol.

    (1996)
  • B.A. Vorderstrasse et al.

    Aryl hydrocarbon receptor-deficient mice generate normal immune responses to model antigens and are resistant to TCDD-induced immune suppression

    Toxicol. Appl. Pharmacol.

    (2001)
  • T.S. Thurmond et al.

    The aryl hydrocarbon receptor has a role in the in vivo maturation of murine bone marrow B lymphocytes and their response to 2,3,7,8-tetrachlorodibenzo-p-dioxin

    Toxicol. Appl. Pharmacol.

    (2000)
  • N.I. Kerkvliet et al.

    Role of the Ah locus in suppression of cytotoxic T lymphocyte activity by halogenated aromatic hydrocarbons (PCBs and TCDD): structure–activity relationships and effects in C57Bl/6 mice congenic at the Ah locus

    Fundam. Appl. Toxicol.

    (1990)
  • D. Davis et al.

    Immunosuppressive activities of polychlorinated dibenzofuran congeners: quantitative structure–activity relationships and interactive effects

    Toxicol. Appl. Pharmacol.

    (1988)
  • A. Vecchi et al.

    Immunosuppressive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in strains of mice with different susceptibility to induction of aryl hydrocarbon hydroxylase

    Toxicol. Appl. Pharmacol.

    (1983)
  • D.J. McConkey et al.

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) kills glucocorticoid-sensitive thymocytes in vivo

    Biochem. Biophys. Res. Commun.

    (1989)
  • A.B. Kamath et al.

    Role of Fas–Fas ligand interactions in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced immunotoxicity: increased resistance of thymocytes from Fas-deficient (lpr) and Fas ligand-defective (gld) mice to TCDD-induced toxicity

    Toxicol. Appl. Pharmacol.

    (1999)
  • Z.W. Lai et al.

    Differential effects of diethylstilbestrol and 2,3,7,8-tetrachlorodibenzo-p-dioxin on thymocyte differentiation, proliferation, and apoptosis in bcl-2 transgenic mouse fetal thymus organ culture

    Toxicol. Appl. Pharmacol.

    (2000)
  • M.S. Denison et al.

    The Ah receptor: a regulator of the biochemical and toxicological actions of structurally diverse chemicals

    Bull. Environ. Contam. Toxicol.

    (1998)
  • Y.Z. Gu et al.

    The PAS superfamily: sensors of environmental and developmental signals

    Annu. Rev. Pharmacol. Toxicol.

    (2000)
  • F.J. Gonzalez et al.

    The aryl hydrocarbon receptor: studies using the AHR-null mice

    Drug Metab. Dispos.

    (1998)
  • J.V. Schmidt et al.

    Ah receptor signaling pathways

    Annu. Rev. Cell Dev. Biol.

    (1996)
  • J.P. Whitlock

    Induction of cytochrome P450 1A1

    Annu. Rev. Pharmacol. Toxicol.

    (1999)
  • O. Hankinson

    The aryl hydrocarbon receptor complex

    Annu. Rev. Pharmacol. Toxicol.

    (1995)
  • M. Karin et al.

    Phosphorylation meets ubiquitination: the control of NF-kappa B activity

    Annu. Rev. Immunol.

    (2000)
  • S. Ghosh et al.

    NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses

    Annu. Rev. Immunol.

    (1998)
  • N. Silverman et al.

    NF-kappa B signaling pathways in mammalian and insect innate immunity

    Genes Dev.

    (2001)
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