The Experts below are selected from a list of 13452 Experts worldwide ranked by ideXlab platform
Agneta Rannug - One of the best experts on this subject based on the ideXlab platform.
-
the Aryl Hydrocarbon Receptor in barrier organ physiology immunology and toxicology
Pharmacological Reviews, 2015Co-Authors: Charlotte Esser, Agneta RannugAbstract:The Aryl Hydrocarbon Receptor (AhR) is an evolutionarily old transcription factor belonging to the Per-ARNT-Sim-basic helix-loop-helix protein family. AhR translocates into the nucleus upon binding of various small molecules into the pocket of its single-ligand binding domain. AhR binding to both xenobiotic and endogenous ligands results in highly cell-specific transcriptome changes and in changes in cellular functions. We discuss here the role of AhR for immune cells of the barrier organs: skin, gut, and lung. Both adaptive and innate immune cells require AhR signaling at critical checkpoints. We also discuss the current two prevailing views-namely, 1) AhR as a promiscuous sensor for small chemicals and 2) a role for AhR as a balancing factor for cell differentiation and function, which is controlled by levels of endogenous high-affinity ligands. AhR signaling is considered a promising drug and preventive target, particularly for cancer, inflammatory, and autoimmune diseases. Therefore, understanding its biology is of great importance.
-
the Aryl Hydrocarbon Receptor mediates uvb radiation induced skin tanning
Journal of Investigative Dermatology, 2011Co-Authors: Bettina Jux, Jean Krutmann, Agneta Rannug, Sandra Luecke, Stephanie Kadow, Charlotte EsserAbstract:Melanogenesis is the vital response to protect skin cells against UVB-induced DNA damage. Melanin is produced by melanocytes, which transfer it to surrounding keratinocytes. Recently, we have shown that the Aryl Hydrocarbon Receptor (AhR) is part of the UVB-stress response in epidermal keratinocytes. UVB triggers AhR signaling by generating the AhR ligand 6-formylindolo(3,2- b )carbazole from tryptophan. We show here that normal murine melanocytes express functional AhR. Using standard UVB tanning protocols, AhR-deficient mice were shown to tan significantly weaker than wild-type mice; in these mice, tyrosinase activity in the epidermis was lower as well. Tanning responses and tyrosinase activity, however, were normal in keratinocyte-specific conditional AhR knockout mice, indicating that release of melanogenic keratinocyte factors is unaffected by the UVB-AhR signaling pathway and that the diminished tanning response in AhR -/- mice is confined to the level of melanocytes. Accordingly, the number of dihydroxyphenylalanin-positive melanocytes increased significantly less on UVB irradiation in AhR -/- mice than in wild-type mice. This difference in melanocyte number was associated with a significantly reduced expression of stem cell factor-1 and c-kit in melanocytes of AhR -/- mice. Thus, the environmental signal sensor AhR links solar UVB radiation to skin pigmentation.
-
the Aryl Hydrocarbon Receptor ahr a novel regulator of human melanogenesis
Pigment Cell & Melanoma Research, 2010Co-Authors: Sandra Luecke, Charlotte Esser, Jean Krutmann, Maria Backlund, Bettina Jux, Agneta RannugAbstract:Skin cancer, chloracne and hyperpigmentation have been associated with the exposure to environmental contaminants such as polychlorinated biphenyls, dioxins or polycyclic aromatic Hydrocarbons. These compounds are xenobiotic high-affinity ligands for the Aryl Hydrocarbon Receptor (AHR), a ligand-activated transcription factor with important physiological roles in, for example, the control of cell proliferation and inflammation. We show here that exposure of normal human melanocytes to the most potent dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), results in activation of the AHR signaling pathway and an AHR-dependent induction of tyrosinase activity, the key enzyme of the melanogenic pathway. In accordance with the upregulation of tyrosinase enzyme activity, total melanin content was also elevated in TCDD-exposed melanocytes. Neither the induction of tyrosinase enzyme activity or of total melanin could be attributed to enhanced cell proliferation, but was rather due to the induction of tyrosinase and tyrosinase-related protein 2 gene expression. Thus, the AHR is able to modulate melanogenesis by controlling the expression of melanogenic genes.
-
cytochrome p450 1a1 gene regulation by uvb involves crosstalk between the Aryl Hydrocarbon Receptor and nuclear factor κb
Chemico-Biological Interactions, 2010Co-Authors: Sandra Luecke, Emma Wincent, Maria Backlund, Ulf Rannug, Agneta RannugAbstract:UVB induces the expression of genes controlled by the Aryl Hydrocarbon Receptor (AhR). a transcription factor that has been implicated in the UV stress response. In this study, we used the human he ...
-
the Aryl Hydrocarbon Receptor in immunity
Trends in Immunology, 2009Co-Authors: Charlotte Esser, Agneta Rannug, Brigitta StockingerAbstract:Low-molecular-weight chemicals or xenobiotics might contribute to the increasing prevalence of allergies and autoimmunity. Certain chemicals can alter immune responses via their action on the cytosolic transcription factor Aryl Hydrocarbon Receptor (AhR). AhR recognizes numerous small xenobiotic and natural molecules, such as dioxin and the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole. Although AhR is best known for mediating dioxin toxicity, knockout studies have indicated that AhR also plays a role in normal physiology, including certain immune responses. In particular, Th17 cells and dendritic cells express high levels of AhR. We review here current evidence for the physiological role of AhR in the immune system, focussing in particular on T-cell biology.
Christopher A Bradfield - One of the best experts on this subject based on the ideXlab platform.
-
an interaction between kynurenine and the Aryl Hydrocarbon Receptor can generate regulatory t cells
Journal of Immunology, 2010Co-Authors: Joshua D Mezrich, John H Fechner, Xiaoji Zhang, Brian P Johnson, William J Burlingham, Christopher A BradfieldAbstract:The Aryl Hydrocarbon Receptor (AHR) has been known to cause immunosuppression after binding dioxin. It has recently been discovered that the Receptor may be central to T cell differentiation into FoxP3 + regulatory T cells (Tregs) versus Th17 cells. In this paper, we demonstrate that kynurenine, the first breakdown product in the IDO-dependent tryptophan degradation pathway, activates the AHR. We furthermore show that this activation leads to AHR-dependent Treg generation. We additionally investigate the dependence of TGF-β on the AHR for optimal Treg generation, which may be secondary to the upregulation of this Receptor that is seen in T cells postexposure to TGF-β. These results shed light on the relationship of IDO to the generation of Tregs, in addition to highlighting the central importance of the AHR in T cell differentiation. All tissues and cells were derived from mice.
-
the Aryl Hydrocarbon Receptor a perspective on potential roles in the immune system
Immunology, 2009Co-Authors: Emily A Stevens, Joshua D Mezrich, Christopher A BradfieldAbstract:The Aryl Hydrocarbon Receptor (AHR) is a protein best known for its role in mediating toxicity. Over 30 years of research has uncovered additional roles for the AHR in xenobiotic metabolism and normal vascular development. Activation of the AHR has long been known to cause immunotoxicity, including thymic involution. Recent data suggesting a role for the AHR in regulatory T-cell (Treg) and T-helper 17 (Th17) cell development have only added to the excitement about this biology. In this review, we will attempt to illustrate what is currently known about AHR biology in the hope that data from fields as diverse as evolutionary biology and pharmacology will help elucidate the mechanism by which AHR modifies immune responses. We also will discuss the complexities of AHR pharmacology and genetics that may influence future studies of AHR in the immune system.
-
a hypomorphic allele of Aryl Hydrocarbon Receptor associated protein 9 produces a phenocopy of the ahr null mouse
Molecular Pharmacology, 2008Co-Authors: Bernice C Lin, Linh P Nguyen, Jacqueline A Walisser, Christopher A BradfieldAbstract:The Aryl Hydrocarbon Receptor-associated protein-9 (ARA9) is a chaperone of the Aryl Hydrocarbon Receptor (AHR). The AHR has been shown to play a late developmental role in the normal closure of a fetal hepatovascular shunt known as the ductus venosus (DV). Given that Ara9-null mice display early embryonic lethality, we generated a hypomorphic Ara9 allele (designated Ara9 fxneo ) that displays reduced ARA9 protein expression. In an effort to demonstrate the role of ARA9 protein in AHR-mediated DV closure, we used combinations of Ara9 wild-type [Ara9(/)], null [Ara9(/)], and hypomorphic [Ara9(fxneo/fxneo)] alleles to produce mice with a graded expression of the ARA9 protein. Liver perfusion studies demonstrated that although none of the Ara9(/) mice displayed a patent DV, the shunt was observed in 10% of the Ara9(/fxneo) mice, 55% of the Ara9(/) mice, and 83% of the Ara9(fxneo/fxneo) mice. That expression level of ARA9 correlates with the frequency of a phenocopy of the Ahr-null allele supports the conclusion that the ARA9 protein is essential for AHR signaling during development.
-
A hypomorphic allele of Aryl Hydrocarbon Receptor-associated protein-9 produces a phenocopy of the Ahr-null
2008Co-Authors: Bernice C Lin, Linh P Nguyen, Jacqueline A Walisser, Christopher A BradfieldAbstract:The Aryl Hydrocarbon Receptor-associated protein-9 (ARA9) is a chaperone of the Aryl Hydrocarbon Receptor (AHR). The AHR has been shown to play a late developmental role in the normal clo-sure of a fetal hepatovascular shunt known as the ductus venosus (DV). Given that Ara9-null mice display early embryonic lethality, we generated a hypomorphic Ara9 allele (designated Ara9fxneo) that displays reduced ARA9 protein expression. In an effort to demonstrate the role of ARA9 protein in AHR-mediated DV clo-sure, we used combinations of Ara9 wild-type [Ara9(/)], null [Ara9(/)], and hypomorphic [Ara9(fxneo/fxneo)] alleles to pro-duce mice with a graded expression of the ARA9 protein. Liver perfusion studies demonstrated that although none of the Ara9(/) mice displayed a patent DV, the shunt was observed in 10 % of the Ara9(/fxneo) mice, 55 % of the Ara9(/) mice, and 83 % of the Ara9(fxneo/fxneo) mice. That expression level of ARA9 correlates with the frequency of a phenocopy of the Ahr-null allele supports the conclusion that the ARA9 protein is essential for AHR signaling during development. The Aryl Hydrocarbon Receptor (AHR) is a ligand-activated transcription factor best known for mediating the adaptive and toxic responses to polycyclic aromatic Hydrocarbons and halogenated dibenzo-p-dioxins (Poland, 1982; Eisen et al., 1983). Once ligands such as these bind the Receptor, the complex translocates to the nucleus in which the AHR disso-ciates and dimerizes with its transcriptional partner, the Aryl Hydrocarbon Receptor nuclear translocator (ARNT). In the nucleus, the AHR/ARNT dimer binds to cognate “dioxin-responsive elements ” in the enhancer regions of responsive genes, resulting in the transcriptional up-regulation of those genes (Reyes et al., 1992; Henry and Gasiewicz, 1993; Hord and Perdew, 1994). The effects mediated by this pathway include the adaptive up-regulation of certain cytochromes P450, as well as toxic endpoints that include thymic involu-tion, hepatocellular damage, and cleft palate (Poland an
-
the search for endogenous activators of the Aryl Hydrocarbon Receptor
Chemical Research in Toxicology, 2008Co-Authors: Linh P Nguyen, Christopher A BradfieldAbstract:The primary design of this perspective is to describe the major ligand classes of the Aryl Hydrocarbon Receptor (AHR). A grander objective is to provide models that may help define the physiological activator or “endogenous ligand” of the AHR. We present evidence supporting a developmental role for the AHR and propose mechanisms by which an endogenous ligand and consequent AHR activation might be important during normal physiology and development. From this vista, we survey the known xenobiotic, endogenous, dietary, and “unconventional” activators of the AHR, including, when possible, information about their induction potency, Receptor binding affinity, and potential for exposure. In light of the essential function of the AHR in embryonic development, we discuss the candidacy of each of these compounds as physiologically important activators.
Nathaniel L Scholz - One of the best experts on this subject based on the ideXlab platform.
-
Aryl Hydrocarbon Receptor independent toxicity of weathered crude oil during fish development
Environmental Health Perspectives, 2005Co-Authors: John P Incardona, Hiroki Teraoka, Mark G Carls, Catherine A Sloan, Tracy K Collier, Nathaniel L ScholzAbstract:Polycyclic aromatic Hydrocarbons (PAHs), derived largely from fossil fuels and their combustion, are pervasive contaminants in rivers, lakes, and nearshore marine habitats. Studies after the Exxon Valdez oil spill demonstrated that fish embryos exposed to low levels of PAHs in weathered crude oil develop a syndrome of edema and craniofacial and body axis defects. Although mechanisms leading to these defects are poorly understood, it is widely held that PAH toxicity is linked to Aryl Hydrocarbon Receptor (AhR) binding and cytochrome P450 1A (CYP1A) induction. Using zebrafish embryos, we show that the weathered crude oil syndrome is distinct from the well-characterized AhR-dependent effects of dioxin toxicity. Blockade of AhR pathway components with antisense morpholino oligonucleotides demonstrated that the key developmental defects induced by weathered crude oil exposure are mediated by low-molecular-weight tricyclic PAHs through AhR-independent disruption of cardiovascular function and morphogenesis. These findings have multiple implications for the assessment of PAH impacts on coastal habitats.
-
Aryl Hydrocarbon Receptor independent toxicity of weathered crude oil during fish development
Environmental Health Perspectives, 2005Co-Authors: John P Incardona, Hiroki Teraoka, Mark G Carls, Catherine A Sloan, Tracy K Collier, Nathaniel L ScholzAbstract:Polycyclic aromatic Hydrocarbons (PAHs), derived largely from fossil fuels and their combustion, are pervasive contaminants in rivers, lakes, and nearshore marine habitats. Studies after the Exxon Valdez oil spill demonstrated that fish embryos exposed to low levels of PAHs in weathered crude oil develop a syndrome of edema and craniofacial and body axis defects. Although mechanisms leading to these defects are poorly understood, it is widely held that PAH toxicity is linked to Aryl Hydrocarbon Receptor (AhR) binding and cytochrome P450 1A (CYP1A) induction. Using zebrafish embryos, we show that the weathered crude oil syndrome is distinct from the well-characterized AhR-dependent effects of dioxin toxicity. Blockade of AhR pathway components with antisense morpholino oligonucleotides demonstrated that the key developmental defects induced by weathered crude oil exposure are mediated by low-molecular-weight tricyclic PAHs through AhR-independent disruption of cardiovascular function and morphogenesis. These findings have multiple implications for the assessment of PAH impacts on coastal habitats.
Sandra Ceccatelli - One of the best experts on this subject based on the ideXlab platform.
-
effect of 2 3 7 8 tetrachlorodibenzo p dioxin on the expression of cytochrome p450 1a1 the Aryl Hydrocarbon Receptor and the Aryl Hydrocarbon Receptor nuclear translocator in rat brain and pituitary
Toxicology and Applied Pharmacology, 2000Co-Authors: Ping Huang, Agneta Rannug, Eva Ahlbom, Helen Hakansson, Sandra CeccatelliAbstract:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related substances are ubiquitous environmental pollutants causing a wide variety of pathological alterations, with the most severe being progressive anorexia and body weight loss. These features suggest a possible involvement of the nervous system and neuroendocrine-related organs including the pituitary gland. However, so far there is little evidence for direct effects of TCDD on these areas. In the present study, male Sprague–Dawley rats were treated with a single oral dose of TCDD (10 μg/kg) and euthanized 1, 3, or 28 days after treatment. The expression of cytochrome P450 1A1 (CYP1A1), the Aryl Hydrocarbon Receptor (AHR), and the Aryl Hydrocarbon Receptor nuclear translocator (ARNT) were analyzed in different brain regions and pituitaries using semiquantitative RT–PCR and Western blotting. Relative levels of CYP1A1 mRNA and protein were dramatically increased in the pituitary. A significant increase in CYP1A1 mRNA was also detected in all the brain regions examined including olfactory bulb, striatum–caudate, hypothalamus, hippocampus, cortex, cerebellum, and substantia nigra. The increase in the expression was time-dependent with the highest level observed 1 day after TCDD treatment. The AHR and ARNT mRNAs were detected in the same areas but in contrast to CYP1A1 the changes in AHR and ARNT mRNA expression were limited to the 28-day time point. The present results provide evidence for the presence of CYP1A1, AHR, and ARNT in the central nervous system and in the pituitary, suggesting that TCDD may exert a direct effect on these regions.
John P Incardona - One of the best experts on this subject based on the ideXlab platform.
-
Aryl Hydrocarbon Receptor independent toxicity of weathered crude oil during fish development
Environmental Health Perspectives, 2005Co-Authors: John P Incardona, Hiroki Teraoka, Mark G Carls, Catherine A Sloan, Tracy K Collier, Nathaniel L ScholzAbstract:Polycyclic aromatic Hydrocarbons (PAHs), derived largely from fossil fuels and their combustion, are pervasive contaminants in rivers, lakes, and nearshore marine habitats. Studies after the Exxon Valdez oil spill demonstrated that fish embryos exposed to low levels of PAHs in weathered crude oil develop a syndrome of edema and craniofacial and body axis defects. Although mechanisms leading to these defects are poorly understood, it is widely held that PAH toxicity is linked to Aryl Hydrocarbon Receptor (AhR) binding and cytochrome P450 1A (CYP1A) induction. Using zebrafish embryos, we show that the weathered crude oil syndrome is distinct from the well-characterized AhR-dependent effects of dioxin toxicity. Blockade of AhR pathway components with antisense morpholino oligonucleotides demonstrated that the key developmental defects induced by weathered crude oil exposure are mediated by low-molecular-weight tricyclic PAHs through AhR-independent disruption of cardiovascular function and morphogenesis. These findings have multiple implications for the assessment of PAH impacts on coastal habitats.
-
Aryl Hydrocarbon Receptor independent toxicity of weathered crude oil during fish development
Environmental Health Perspectives, 2005Co-Authors: John P Incardona, Hiroki Teraoka, Mark G Carls, Catherine A Sloan, Tracy K Collier, Nathaniel L ScholzAbstract:Polycyclic aromatic Hydrocarbons (PAHs), derived largely from fossil fuels and their combustion, are pervasive contaminants in rivers, lakes, and nearshore marine habitats. Studies after the Exxon Valdez oil spill demonstrated that fish embryos exposed to low levels of PAHs in weathered crude oil develop a syndrome of edema and craniofacial and body axis defects. Although mechanisms leading to these defects are poorly understood, it is widely held that PAH toxicity is linked to Aryl Hydrocarbon Receptor (AhR) binding and cytochrome P450 1A (CYP1A) induction. Using zebrafish embryos, we show that the weathered crude oil syndrome is distinct from the well-characterized AhR-dependent effects of dioxin toxicity. Blockade of AhR pathway components with antisense morpholino oligonucleotides demonstrated that the key developmental defects induced by weathered crude oil exposure are mediated by low-molecular-weight tricyclic PAHs through AhR-independent disruption of cardiovascular function and morphogenesis. These findings have multiple implications for the assessment of PAH impacts on coastal habitats.
