title: Aryl Hydrocarbon Receptor Activation Synergistically Induces Lipopolysaccharide-Mediated Expression of Proinflammatory Chemokine (c-c motif) Ligand 20.
abstract: The Ah receptor (AHR) is directly involved in the regulation of both innate and adaptive immunity. However, these activities are poorly understood at the level of gene regulation. The chemokine (c-c motif) ligand 20 (CCL20) plays a nonredundant role in the chemoattraction of C-C motif receptor 6 expressing cells (eg, T cells and others). A survey of promoter regions of chemokine genes revealed that there are several putative dioxin responsive elements in the mouse Ccl20 promoter. The addition of an AHR agonist along with lipopolysaccharide (LPS) to cultured primary peritoneal macrophages results in synergistic induction of both Ccl20 mRNA and protein, compared with each compound alone. Through the use of macrophage cultures derived from Ahr(-) (/) (-) and Ahr(nls/nls) mice, it was established that expression of the AHR and its ability to translocate into the nucleus are necessary for AHR ligand-mediated synergistic induction of Ccl20. Gel shift analysis determined that a potent tandem AHR binding site ~3.1 kb upstream from the transcriptional start site can efficiently bind the AHR/ARNT (aryl hydrocarbon receptor/AHR nuclear translocator) heterodimer upon activation with a number of AHR agonists. Furthermore, studies reveal that LPS increases AHR levels on the Ccl20 promoter while decreasing HDAC1 occupancy. The level of Ccl20 constitutive expression in the colon is greatly attenuated in Ahr(-) (/) (-) mice. These studies suggest that the presence of AHR ligands during localized inflammation may augment chemokine expression, thus participating in the overall response to pathogens.
authors.affiliation: Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, Penn State University, University Park, Pennsylvania 16802.
authors.forename: Tejas S
authors.initials: TS
authors.lastname: Lahoti
authors.affiliation: Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, Penn State University, University Park, Pennsylvania 16802.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Boyer
authors.affiliation: Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, Penn State University, University Park, Pennsylvania 16802.
authors.forename: Ann
authors.initials: A
authors.lastname: Kusnadi
authors.affiliation: Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, Penn State University, University Park, Pennsylvania 16802.
authors.forename: Gulsum E
authors.initials: GE
authors.lastname: Muku
authors.affiliation: Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, Penn State University, University Park, Pennsylvania 16802.
authors.forename: Iain A
authors.initials: IA
authors.lastname: Murray
authors.affiliation: Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, Penn State University, University Park, Pennsylvania 16802 ghp2@psu.edu.
authors.forename: Gary H
authors.initials: GH
authors.lastname: Perdew
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000483:Alleles; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D002227:Carbazoles / Q000633:toxicity; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D003433:Crosses, Genetic; D004357:Drug Synergism; D004785:Environmental Pollutants / Q000633:toxicity; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000819:agonists* / Q000633:toxicity; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D002227:Carbazoles; D054418:Chemokine CCL20; D004785:Environmental Pollutants; D056284:Histone Deacetylase 1; D008024:Ligands; D008070:Lipopolysaccharides; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse; C497397:Arnt protein, mouse; C493447:CCL20 protein, mouse; C075954:indolo(3,2-b)carbazole; C484389:Hdac1 protein, mouse
keywords: AHR agonists; aryl hydrocarbon receptor; chemokine; chemokine (c–c motif); ligand 20; lipopolysaccharide; macrophages