title: Endogenous ligands of the aryl hydrocarbon receptor regulate lung dendritic cell function.
abstract: The aryl hydrocarbon receptor (AhR) is a transcription factor that has been extensively studied as a regulator of toxicant metabolism. However, recent evidence indicates that the AhR also plays an important role in immunity. We hypothesized that the AhR is a novel, immune regulator of T helper type 2 (Th2) -mediated allergic airway disease. Here, we report that AhR-deficient mice develop increased allergic responses to the model allergen ovalbumin (OVA), which are driven in part by increased dendritic cell (DC) functional activation. AhR knockout (AhR(-/-) ) mice sensitized and challenged with OVA develop an increased inflammatory response in the lung compared with wild-type controls, with greater numbers of inflammatory eosinophils and neutrophils, greater T-cell proliferation, greater production of Th2 cytokines, and higher levels of OVA-specific IgE and IgG1. Lung DCs from AhR(-/-) mice stimulated antigen-specific proliferation and Th2 cytokine production by naive T cells in vitro. Additionally, AhR(-/-) DCs produced higher levels of tumour necrosis factor-α and interleukin-6, which promote Th2 differentiation, and expressed higher cell surface levels of stimulatory MHC Class II and CD86 molecules. Overall, loss of the AhR was associated with enhanced T-cell activation by pulmonary DCs and heightened pro-inflammatory allergic responses. This suggests that endogenous AhR ligands are involved in the normal regulation of Th2-mediated immunity in the lung via a DC-dependent mechanism. Therefore, the AhR may represent an important target for therapeutic intervention in allergic airways inflammation.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Rochester, Rochester, NY, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Thatcher
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Rochester, Rochester, NY, USA.|Department of Environmental Medicine, University of Rochester, Rochester, NY, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Williams
authors.affiliation: Department of Environmental Medicine, University of Rochester, Rochester, NY, USA.|Lung Biology and Disease Program, University of Rochester, Rochester, NY, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pollock
authors.affiliation: Department of Environmental Medicine, University of Rochester, Rochester, NY, USA.
authors.forename: Claire E
authors.initials: CE
authors.lastname: McCarthy
authors.affiliation: Department of Environmental Medicine, University of Rochester, Rochester, NY, USA.
authors.forename: Shannon H
authors.initials: SH
authors.lastname: Lacy
authors.affiliation: Department of Environmental Medicine, University of Rochester, Rochester, NY, USA.|Lung Biology and Disease Program, University of Rochester, Rochester, NY, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Rochester, Rochester, NY, USA.|Department of Environmental Medicine, University of Rochester, Rochester, NY, USA.|Lung Biology and Disease Program, University of Rochester, Rochester, NY, USA.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Sime
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D007111:Immunity, Cellular; D018928:Immunity, Mucosal; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002227:Carbazoles; D016207:Cytokines; D018836:Inflammation Mediators; D008024:Ligands; D010047:Ovalbumin; D018336:Receptors, Aryl Hydrocarbon; C111855:6-formylindolo(3,2-b)carbazole; C484722:Ahr protein, mouse
keywords: T helper type 1/type 2 cells; allergy; antigen presentation/processing; dendritic cells; lung