The aryl hydrocarbon receptor: Regulation of hematopoiesis and involvement in the progression of blood diseases

Department of Environmental Medicine, University of Rochester School of Medicine, 601 Elmwood Avenue, Box EHSC, Rochester, NY 14642, USA.
Blood Cells Molecules and Diseases (Impact Factor: 2.33). 02/2010; 44(4):199-206. DOI: 10.1016/j.bcmd.2010.01.005
Source: PubMed

ABSTRACT The aryl hydrocarbon receptor (AhR) is a basic helix-loop-helix protein that belongs to the superfamily of environment-sensing PAS (Per-ARNT-Sim) proteins. A large number of ligands have been described to bind AhR and promote its nuclear translocation. In the nucleus, the AhR and its dimerization partner the AhR nuclear translocator (ARNT) form a DNA-binding complex that acts as a transcriptional regulator. Animal and human data suggest that, beyond its mediating responses to xenobiotic and/or unknown endogenous ligands, the AhR has a role, although as yet undefined, in the regulation of cell cycle and inflammation. The AhR also appears to regulate the hematopoietic and immune systems during development and adult life in a cell-specific manner. While accidental exposure to xenobiotic AhR ligands has been associated with leukemia in humans, the specific mechanisms of AhR involvement are still not completely understood. However, recent data are consistent with a functional role of the AhR in the maintenance of hematopoietic stem and/or progenitor cells (HSCs/HPCs). Studies highlighting AhR regulation of HSCs/HPCs provide a rational framework to understand their biology, a role of the AhR in hematopoietic diseases, and a means to develop interventions for these diseases.


Available from: Kameshwar P Singh, Jun 11, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The aryl hydrocarbon receptor (AHR), a multifunctional protein and a key regulator of drug metabolizing enzymes, belongs to the basic-helix-loop-helix (bHLH)/PAS (Per- Arnt-Sim) super-family of transcription factors. The AHR responds to exogenous and endogenous chemicals by induction or repression of a large number of genes involved in many physiological processes and normal development. The diverse spectrum of AHR activators from well-known planar hydrophobic halogenated aromatic hydrocarbons (HAHs) to chemical compounds whose structure and physicochemical properties are very different from classical AHR ligands suggests that the AHR has a tremendously promiscuous ligand binding pocket. Due to the absence of a 3D structure of the ligand binding domain, promiscuity of the AHR has remained elusive. However, increasing experimental evidence indicate that the non- typical AHR ligands might activate the AHR signaling pathway indirectly by inhibiting the metabolic turnover of an endogenous ligand of the AHR. Therefore, the objective of this thesis was to characterize the inhibition of degradation of 6-formylindolo[3,2- b]carbazole (FICZ), the suggested natural high affinity AHR ligand, as a mechanism that could explain the earlier described agonistic properties of structurally very diverse AHR activators. The obtained results show that FICZ is a potent AHR agonist in vitro and in vivo which can distribute to the body through systemic circulation and induce cytochrome P450 1A1 (CYP1A1) the prototypical AHR target in various organs. The studies presented in this thesis demonstrate that if the metabolic clearance of FICZ is compromised, femtomolar concentrations of FICZ are sufficient to activate AHR signaling. The AHR signaling pathway seems to be sensitive to oxidative stress but the redox regulation of AHR has not been well characterized. Studies on dioxin and other reactive oxygen species (ROS) producing agents have demonstrated that the AHR is a mediator of oxidative stress. Indeed, AHR works in close concert with the master regulator of antioxidant responses, nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Multiple sources of ROS appear to be involved in modulating AHR signaling and probably via three major systems, microsomes, mitochondria and NADPH oxidase enzymes (NOXs). Furthermore, it has been observed that many environmental pollutants, including metals and other NOX-activators increase the levels of the diffusible molecule hydrogen peroxide (H2O2) and change the cellular redox status and thereby interfere with cell growth kinetics and the endogenous functions of the AHR. To increase the understanding of downstream adaptive responses to oxidative stress, including up-regulation of antioxidant genes and modulation of AHR signaling was another objective of this work. The findings demonstrate that superoxide anion (O2−.) or H2O2 produced by NOXs can negatively and positively modulate the AHR signaling pathway. The importance of cellular redox levels which can influence endogenously activated AHR signaling broadens our earlier knowledge and explains why many oxidants behave both as AHR antagonists and agonists. In summary, this thesis extends the mechanistic understanding of the promiscuity of AHR and provides important information with regard to the redox regulation of AHR endogenous signaling
    Edited by Afshin Mohammadi Bardbori, 05/2013; Karolinska Institutet., ISBN: 978-91-7549-163-9
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor historically studied for its role in environmental chemical-mediated toxicity and carcinogenicity. In the last 5 years, however, it has become clear that the AhR, presumably activated by endogenous ligand(s), plays an important role in immune system development and function. Other articles in this edition summarize AhR function during T cell and antigen-presenting cell development and function, including the effects of AhR activation on dendritic cell function, T cell skewing, inflammation, and autoimmune disease. Here, we focus on AhR expression and function during B cell differentiation. Studies exploiting immunosuppressive environmental chemicals to probe the role of the AhR in humoral immunity are also reviewed to illustrate the multiple levels at which a "nominally activated" AhR could control B cell differentiation from the hematopoietic stem cell through the pro-B cell, mature B cell, and antibody-secreting plasma cell stages. Finally, a putative role for the AhR in the basic biology of B cell malignancies, many of which have been associated with exposure to environmental AhR ligands, is discussed.
    Seminars in Immunopathology 08/2013; 35(6). DOI:10.1007/s00281-013-0390-8 · 6.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Polycyclic aromatic hydrocarbons, such as 7,12-dimethylbenz(a)anthracene (DMBA), are environmental pollutants that exert multiple toxic and carcinogenic effects. Studies showed that these effects are mediated by activation of the aryl hydrocarbon receptor (AhR) and modulated by allelic variants of Ahr gene. Here, we investigated the effects of DMBA treatment in the inflammatory response and bone marrow (BM) hematopoietic function of maximal acute inflammatory response (AIRmax) and minimal acute inflammatory response (AIRmin) heterogeneous mouse lines selected for high and low acute inflammatory responsiveness, respectively. The phenotypic selection resulted in the segregation of the Ahr(d) and Ahr(b1) alleles that confer low and high receptor ligand-binding affinity, respectively, in AIRmax and AIRmin mice. We observed a reduction in BM mature granulocyte population in AIRmin mice 24 hours after DMBA treatment while both blast and immature myeloid cells were increased. Proliferation and differentiation of BM myeloid cells in response to in vitro granulocyte-macrophage colony-stimulating factor stimulus were impaired in AIRmin-treated mice. These DMBA effects on myeloid BM cells (BMCs) affected the in vivo leukocyte migration to an inflammatory site induced by polyacrylamide beads (Biogel P-100, Bio-Rad, France) injection in AIRmin mice. On the other hand, these alterations were not observed in DMBA-treated AIRmax mice. These data indicate that DMBA affects myeloid cell differentiation and inflammatory response and Ahr(b1) allele in the genetic background of AIRmin mice contributes to this effect.
    International Journal of Toxicology 02/2014; 33(2). DOI:10.1177/1091581814522837 · 1.23 Impact Factor