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: 2.65). 02/2010; 44(4):199-206. DOI: 10.1016/j.bcmd.2010.01.005
Source: PubMed


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.

Download full-text


Available from: Kameshwar P Singh
  • Source
    • "Several studies indicate that murine and human HSC express modest AhR levels [98–100] and recent breakthrough studies indicate that the AhR plays a critical role in HSC growth and differentiation [95, 101–105]. For example, in vivo AhR modulation disrupts HSC growth, senescence, and migration [95, 101–103, 106, 107]. Of note is that most of these studies used environmental AhR ligands as probes to establish the nominal function of the AhR in HSCs [101, 102, 104, 106, 107]. "
    [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.
    Full-text · Article · Aug 2013 · Seminars in Immunopathology
  • Source
    • "AhR participates in NF-κB signalling pathways regulating inflammation , immune responses, apoptosis, survival, and probably other functions. This aspect of biological roles of AhR is not clearly described and well known (Kung et al., 2009; Puga et al., 2009; Casado et al., 2010; Quintana & Sherr 2013; Nguyen 2013). A toxic potential of a chemical is related to its initial interaction with the target cell plasma membrane. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Metabolism of polyunsaturated fatty acids results in biosynthesis of mediators with different physiological effects. These metabolites include prostaglandins, prostacyclins, isoprostanes and others that are important signalling molecules and regulate a variety of physiological and pathophysiological processes including inflammation. Prostaglandins and isoprostanes are produced by either non-enzymatic lipid peroxidation or by enzyme-induced peroxidation (cyclooxygenases and lipoxygenases). They are used as biomarkers of oxidative stress. The aim of our study was to assess the effect of eicosapentaenoic acid (EPA) supplementation with added benzo(a)pyrene (BaP) on HepG2 cells by using a UHPLC/MS-TOF method. This rapid and simple method was developed for the identification, separation and quantification of 8-iPGF3α, PGF3α, 8-isoPGF2α and 5-iPF2α in cultured cells. The UHPLC/MS-TOF method was validated. The calculated limit of detection was in the range of 0.16-0.50 ng/mL, precision (% RSD): 1.2-2.1% and recoveries better than 88%. This method empowered qualitative and quantitative analysis of the selected individual prostaglandins derived from arachidonic acid and eicosapentaenoic acid from cell extracts.
    Full-text · Article · Jan 2013 · Acta biochimica Polonica
  • Source
    • "The mechanisms by which AHR ligands, both exogenous and endogenous, affect these processes are poorly understood but appear to involve multiple interactions between AHR and other signaling pathways. It also is apparent that modulation of AHR via certain agonists and antagonists likely impinges on the pathophysiology of human disease states, such as cardiovascular diseases (Zhang et al., 2010), diabetes (Kerkvliet et al., 2009), cancer (Dietrich and Kaina, 2010), and blood diseases (Casado et al., 2010). Thus, selective pharmacological tools are needed to identify the various roles of AHR ligands, to assess the impact of AHR modulation in preclinical animal models of human diseases, and to determine whether AHR is an appropriate target for novel therapies. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates genes involved in drug/xenobiotic metabolism, cell cycle progression, cell fate determination, immune function, and inflammatory response. Increasing evidence that AHR plays a role in the pathophysiology of a number of human disease states is driving the need for improved pharmacological tools to be used for understanding the in vivo impact of AHR modulation. In this study, we have characterized and used structure-activity relationship analyses of a newly synthesized library of derivatives of the potent AHR antagonist 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH223191). Initial screening of these compounds revealed that those bearing groups with strong electronegativity at the R1 position (i.e., CHD-5, CHD-11, and CHD-12) versus those that are more electron-poor at this position (i.e., CHD-7 and CHD-8) elicited the most potent AHR antagonistic properties. The ability of these derivatives to inhibit agonist (2,3,7,8-tetrachlorodibenzo-p-dioxin) binding, nuclear translocation of AHR, and agonist-induced enzyme activity also were determined and support the initial findings. Furthermore, CH223191, but not CHD-5, CHD-11, or CHD-12, was found to exhibit AHR-independent proproliferative properties. These results contribute to our understanding of the structural requirements of potent AHR antagonists and the development of effective pharmacological tools to be used for studying the pathophysiological role of AHR.
    Full-text · Article · Oct 2011 · Molecular pharmacology
Show more