Abstract
The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is involved in a wide range of critical cellular events in response to endogenous signals or xenobiotics. 2,3,7,8-Tetrachlorodibenzo-para-dioxin (TCDD) is one of the AhR ligands with the maximum affinity for AhR. TCDD is the most toxic among the dioxin xenobiotics and induces a wide range of biological responses, including immunotoxicity and cancer. The complex ligand:AhR:ARNT functions as a transcription factor, binding to the dioxin responsive element (DRE) sequences in the regulatory regions of target genes. Macrophages are key regulators of the innate immune response and being present in all body organs and tissues, they are one of the cell types that are the first to encounter xenobiotics; thus, the insight into the TCDD effect on macrophages is of paramount importance. Putative DREs are predicted using the SITECON software tool in the regulatory regions of the genes encoding transcription factors REL, RELA, and IRF1, expressed in macrophages. The nuclear extract and total RNA are isolated from the U937 macrophage-like cells exposed to 10 nM TCDD (or 0.1% DMSO as the control) for 1, 3, and 6 h. The binding of the TCDD:AhR:ARNT transcription complex from the nuclear extract with double-stranded oligonucleotides containing the putative DREs was studied by the EMSA. Quantitative real-time PCR demonstrates that the expression of these genes in the U937 macrophages increases in a statistically significant manner 1 h (the characteristic time of the maximal dioxin:AhR:ARNT translocation to the nucleus) after exposure to 10 nM TCDD. These results confirm the functional activity of the DREs residing in the IRF1, REL, and RELA regulatory regions via the AhR signaling pathway.
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Biswas, S.K., Chittezhath, M., Shalova, I.N., and Lim, J.Y., Macrophage polarization and plasticity in health and disease, Immunol. Res., 2012, vol. 53, nos. 1/3, pp. 11–24.
Boutros, P.C., Moffat, I.D., Franc, M.A., Tuomisto, J., and Okey, A.B., Dioxin-responsive AHRE-II gene battery: Identification by phylogenetic footprinting, J. Bichem. Biophys. Res. Commun, 2004, vol. 321, no. 3, pp. 707–715.
Connor, K.T. and Aylward, L.L., Human response to dioxin: Aryl hydrocarbon receptor (AhR) molecular structure, function, and dose-response data for enzyme induction indicate an impaired human AhR, J. Toxicol. Environ. Health B Crit. Rev., 2006, vol. 9, no. 2, pp. 147–171.
Denison, M.S. and Nagy, S.R., Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals, Annu. Rev. Pharmacol. Toxicol., 2003, vol. 43, pp. 309–334.
Esser, C., Rannug, A., and Stockinger, B., The aryl hydrocarbon receptor in immunity, Trends Immunol., 2009, vol. 30, no. 9, pp. 447–454. 2009.06.005 doi 10.1016/j.it
Fujii-Kuriyama, Y. and Kawajiri, K., Molecular mechanisms of the physiological functions of the aryl hydrocarbon (dioxin) receptor, a multifunctional regulator that senses and responds to environmental stimuli, Proc. Jpn. Acad. Ser. B, Phys. Biol. Sci., 2010, vol. 86, no. 1, pp. 40–53
Fujita, H., Samejima, H., Kitagawa, N., Mitsuhashi, T., Washio, T., Yonemoto, J., Tomita, M., Takahashi, T., and Kosaki, K., Genome-wide screening of dioxin-responsive genes in fetal brain: Bioinformatic and experimental approaches, Congenital Anomalies, 2006, vol. 46, pp. 135–143.
Furman, D.P., Oshchepkova, E.A., Oshchepkov, D.Yu., Shamanina, M.Yu., and Mordvinov, V.A., Promoters of the genes encoding the transcription factors regulating the cytokine gene expression in macrophages contain putative binding sites for aryl hydrocarbon receptor, Comput. Biol. Chem., 2009, vol. 33, no. 6, pp. 465–468.
Gordon, S. and Taylor, P.R., Monocyte and macrophage heterogeneity, Nat. Rev. Immunol., 2005, vol. 5, no. 12, pp. 953–964.
Hunter, J.E., Leslie, J., and Perkins, N.D., c-Rel and its many roles in cancer: An old story with new twists, Br. J. Cancer, 2016, vol. 114, no. 1, pp. 1–6. doi 10.1038/bjc.2015.410
Kerkvliet, N.I., TCDD: An environmental immunotoxicant reveals a novel pathway of immunoregulation—a 30-year odyssey, Toxicol. Pathol., 2012, vol. 40, no. 2, pp. 138–142.
Komura, K., Hayashi, S., Makino, I., Poellinger, L., and Tanaka, H., Aryl hydrocarbon receptor/dioxin receptor in human monocytes and macrophages, Mol. Cell Biochem., 2001, vol. 226, nos. 1/2, pp. 107–118.
Mandal, P.K., Dioxin: A review of its environmental effects and its aryl hydrocarbon receptor biology, J. Comp. Physiol. B, 2005, vol. 175, pp. 221–230.
Meyer, L.R., Zweig, A.S., Hinrichs, A.S., Karolchik, D., Kuhn, R.M., Wong, M., Sloan, C.A., Rosenbloom, K.R., Roe, G., Rhead, B., Raney, B.J., Pohl, A., Malladi, V.S., Li, C.H., Lee, B.T., et al., The UCSC genome browser database: Extensions and updates 2013, Nucleic Acids Res., 2013, vol. 41, pp. 64–69.
Mulero-Navarro, S. and Fernandez-Salguero, P.M., New trends in Aryl hydrocarbon receptor biology, Front. Cell Dev. Biol., 2016, vol. 4, no. 45. doi 10.3389/fcell.2016.00045
Oshchepkov, D.Y., Kashina, E.V., Antontseva, E.V., Oshchepkova, E.A., Mordvinov, V.A., and Furman, D.P., Dynamics of IL-12 cytokine expression in human macrophages after dioxin exposure, Russ. J. Genetics: Appl. Res., 2014, vol. 4, no. 6, pp. 568–574.
Oshchepkov, D.Y., Vityaev, E.E., Grigorovich, D.A., Ignatieva, E.V., and Khlebodarova, T.M., SITECON: A tool for detecting conservative conformational and physicochemical properties in transcription factor binding site alignments and for site recognition, Nucleic Acids Res., 2004, vol. 32, pp. 208–212.
Sciullo, E.M., Dong, B., Vogel, C.F., and Matsumura, F., Characterization of the pattern of the nongenomic signaling pathway through which TCDD-induces early inflammatory responses in U937 human macrophages, Chemosphere, 2009, vol. 74, no. 11, pp. 1531–1537.
Sun, Y.V., Boverhof, D.R., Burgoon, L.D., Fielden, M.R., and Zacharewski, T.R., Comparative analysis of dioxin response elements in human, mouse and rat genomic sequences, Nucleic Acids Res., 2004, vol. 32, pp. 4512–4523.
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Original Russian Text © E.V. Kashina, D.Y. Oshchepkov, E.V. Antontseva, M.Y. Shamanina, D.P. Furman, V.A. Mordvinov, 2016, published in Vavilovskii Zhurnal Genetiki i Selektsii, 2016, Vol. 20, No. 6, pp. 894–898.
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Kashina, E.V., Oshchepkov, D.Y., Antontseva, E.V. et al. Expression dynamics of the REL, RELA, and IRF1 transcription factors in U937 macrophages after dioxin exposure. Russ J Genet Appl Res 7, 580–584 (2017). https://doi.org/10.1134/S2079059717050082
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DOI: https://doi.org/10.1134/S2079059717050082