Endogenous Functions of the Aryl Hydrocarbon Receptor (AHR): Intersection of Cytochrome P450 1 (CYP1)-metabolized Eicosanoids and AHR Biology

Nebert, Daniel W.; Karp, Christopher L.

doi:10.1074/jbc.r800053200

Cited by 144 publications

(126 citation statements)

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“…Electron microscopy studies might help elucidate this hypothesis. Alternatively, loss of cell-type CYP1A1 expression might cause alterations in eicosanoid homeostasis (for review, see Nebert and Karp, 2008); changes in the balance of any one of the more than 150 eicosanoids could lead to many types of subcellular dysregulation.…”

Section: Discussionmentioning

confidence: 99%

“…PAHs are typically activated metabolically by phase I enzymes to reactive intermediates that bind covalently to nucleic acids and proteins; however, PAHs are also detoxified (Uno et al, 2004(Uno et al, , 2006 by phase I (functionalization) as well as by phase II (conjugation) enzymes (Pelkonen and Nebert, 1982;Conney et al, 1994). In addition, PAHs elicit the up-and down-regulation of hundreds of other genes via both AHR-dependent and -independent mechanisms (Nebert, 1989;Nebert et al, 2000bNebert et al, , 2004Puga et al, 2000;Miller and Ramos, 2001;Nebert and Karp, 2008).…”

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confidence: 99%

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Organ-Specific Roles of CYP1A1 during Detoxication of Dietary Benzo[a]pyrene

Shi¹,

Dragin²,

Gálvez-Peralta³

et al. 2010

Molecular Pharmacology

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Polycyclic aromatic hydrocarbons (PAHs) are widely distributed environmental toxicants derived from sources that include cigarette smoke, petroleum distillation, gas-and diesel-engine exhaust, and charcoal-grilled food. The gastrointestinal tract is the principal route of PAH exposures, even when inhaled. The most thoroughly studied prototype of PAHs is benzo[a]pyrene (BaP), well known to be toxic, mutagenic, and carcinogenic in various tissues and cell types. This lab has previously shown that Cyp1a1(Ϫ/Ϫ) global knockout mice treated by oral administration of BaP die at 28 to 32 days with immunosuppression, whereas wild-type mice remain healthy for 1 year on high BaP doses (125 mg/kg/day). Thus, for oral BaP, CYP1A1 is more important in detoxication than in metabolic activation. After several days of oral BaP, we found surprisingly low CYP1A1 levels in liver, compared with that in small intestine; we postulated that this finding might reflect efficient detoxication of oral BaP in proximal small intestine such that significant amounts of the inducer BaP no longer reach the liver. In the present study, many parameters were therefore compared in wild-type, Cyp1a1(Ϫ/Ϫ) global knockout, intestinal epithelial cell-specific Cyp1a1 knockout, and hepatocyte-specific Cyp1a1 knockout mice as a function of long-term oral exposure to BaP. The peak of CYP1A1 (mRNA, protein) expression in liver occurred at 12 h, whereas highly induced CYP1A1 in small intestine persisted throughout the 30-day experiment. Hepatocyte-specific Cyp1a1 knockout mice remained as healthy as wild-type mice; intestinal epithelial cell-specific Cyp1a1 knockout mice behaved like Cyp1a1(Ϫ/Ϫ) mice, dying with immunosuppression ϳ30 days on oral BaP. We conclude that small intestine CYP1A1, and not liver CYP1A1, is critically important in oral BaP detoxication.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Organ-Specific Roles of CYP1A1 during Detoxication of Dietary Benzo[a]pyrene

Shi¹,

Dragin²,

Gálvez-Peralta³

et al. 2010

Molecular Pharmacology

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“…For many years, investigators have reported an apparent correlation between outcomes seen in AhR 2/2 mice or after xenobiotic activation of the AhR and functions controlled by arachidonic acid metabolites, particularly inflammatory responses (Nebert and Karp, 2008). However, the exact mechanisms responsible for this association have been difficult to define, although some studies suggest that AhR activation by eicosanoids is responsible.…”

Section: Arachidonic Acid Metabolitesmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Control of Adaptive Immunity

Quintana

Sherr²

2013

Pharmacological Reviews

278

253

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“…Upon ligand-binding, AHR translocates into the nucleus where it regulates the expression of a variety of genes, including the xenobiotic metabolizing enzyme cytochrome P450A1 (CYP1A1) [23]. AHR binds to, and is activated by a range of structurally divergent chemicals including natural dietary, endogenous ligands, and synthetic environmental agents among which dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)) is the most extensively studied pure agonist [23,24]. In the mouse, AHR is reported to regulate Th17 and Treg differentiation in ligand-specific fashion [25][26][27] and natural AHR agonists favor Th17 differentiation in vitro and enhanced IL-22 production [27][28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL‐22 and IL‐17 production by human T helper cells

Ramirez¹,

Brembilla²,

Sorg³

et al. 2010

Eur J Immunol

165

141

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Ligands of the aryl hydrocarbon receptor (AHR), a transcription factor mediating the effects of dioxin, favor Th17 differentiation and exacerbate autoimmunity in mice. We investigated how AHR ligands affected human T-cell polarization. We found that the high affinity and stable AHR-ligand dioxin as well as the natural AHR-ligand 6-formylinolo [3,2-b] carbazole induced the downstream AHR-target cytochrome P450A1, and without affecting IFN-c, they enhanced IL-22 while simultaneously decreasing IL-17A production by CD4 1 T cells. The specific AHRinhibitor CH-223191 abolished these effects. Furthermore, blockade of IL-23 and IL-1, important for Th17 expansion, profoundly decreased IL-17A but not IL-22 production. AHR agonists reduced the expression of the Th17 master transcription factor retinoic acid-related orphan receptor C (RORC), without affecting T-bet, GATA-3 and Foxp3. They also decreased the expression of the IL-23 receptor. Importantly, AHR-ligation did not only decrease the number of Th17 cells but also primed naïve CD4 1 T cells to produce IL-22 without IL-17 and IFN-c. Furthermore, IL-22 single producers did not express CD161, which distinguished them from the CD161 1 Th17 cells. Hence, our data provide compelling evidence that AHR activation participates in shaping human CD4 1 T-cell polarization favoring the emergence of a distinct subset of IL-22-producing cells that are independent from the Th17 lineage. IntroductionLocal cytokine milieu during antigen presentation profoundly affects the differentiation program of CD4 1 T cells [1]. In the mouse, TGF-b, in the presence of IL-6 and pro-inflammatory cytokines, favors the emergence of Th17 cells that produce IL-17 and express the master transcription factor retinoic acid-related orphan receptor (ROR)gt [2][3][4][5][6]. Th17 cells are expanded and terminally differentiated in the presence of . Human Th17 cells may be generated in the presence of IL-1 and IL-23; IL-1 and IL-6; or . Th17 cells express CCR6 and 2450produce the CCR6-ligand CCL20, thereby amplifying Th17 cell recruitment at sites of inflammation [11]. IL-22, a member of the IL-10-family, is produced by Th17 cells, and to some extent by Th1 cells, NKT cells, NK cells and lymphoid tissue inducer-like cells [12]. IL-22 signals via a receptor consisting of IL-22R and IL-10R2 subunits [11]. Cells of hemapoietic origin do not express IL-22R; instead, IL-2R is highly expressed by epithelial cells of the gastrointestinal tract and the skin. In the mouse, IL-23 was shown to drive preferential expansion of cells that co-express IL-22 and IL-17, that may synergize to augment the expression of genes involved in defense against microbial pathogens [13,14]. However, several mouse models of infection and autoimmunity suggested distinct roles for .In addition to cytokines, other mediators may impact CD4 1 T-cell differentiation. We and others have shown that prostaglandin E2 (PGE2) favors human Th17 expansion [20][21][22]. Furthermore, ligands of the aryl hydrocarbon receptor (AHR) exert a role. AHR is a...

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Endogenous Functions of the Aryl Hydrocarbon Receptor (AHR): Intersection of Cytochrome P450 1 (CYP1)-metabolized Eicosanoids and AHR Biology

Cited by 144 publications

References 70 publications

Organ-Specific Roles of CYP1A1 during Detoxication of Dietary Benzo[a]pyrene

Organ-Specific Roles of CYP1A1 during Detoxication of Dietary Benzo[a]pyrene

Aryl Hydrocarbon Receptor Control of Adaptive Immunity

Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL‐22 and IL‐17 production by human T helper cells

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