title: Differential consequences of two distinct AhR ligands on innate and adaptive immune responses to influenza A virus.
abstract: Immune modulation by the aryl hydrocarbon receptor (AhR) has been primarily studied using 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). Recent reports suggest another AhR ligand, 6-formylindolo[3,2-b]carbazole (FICZ), exhibits distinct immunomodulatory properties, but side-by-side comparisons of these 2 structurally distinct, high-affinity ligands are limited. In this study, the effects of in vivo AhR activation with TCDD and FICZ were directly compared in a mouse model of influenza virus infection using 3 key measures of the host response to infection: pulmonary neutrophilia, inducible nitric oxide synthase (iNOS) levels, and the virus-specific CD8(+) T-cell response. By this approach, the consequences of AhR activation on innate and adaptive immune responses to the same antigenic challenge were compared. A single dose of TCDD elicited AhR activation that is sustained for the duration of the host's response to infection and modulated all 3 responses to infection. In contrast, a single dose of FICZ induced transient AhR activation and had no effect on the immune response to infection. Micro-osmotic pumps and Cyp1a1-deficient mice were utilized to augment FICZ-mediated AhR activation in vivo, in order to assess the effect of transient versus prolonged AhR activation. Prolonged AhR activation with FICZ did not affect neutrophil recruitment or pulmonary iNOS levels. However, FICZ-mediated AhR activation diminished the CD8(+) T-cell response in Cyp1a1-deficient mice in a similar manner to TCDD. These results demonstrate that immunomodulatory differences in the action of these 2 ligands are likely due to not only the duration of AhR activation but also the cell types in which the receptor is activated.
authors.affiliation: Department of Environmental Medicine and Toxicology Graduate Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
authors.forename: Jennifer L H
authors.initials: JL
authors.lastname: Wheeler
authors.forename: Kyle C
authors.initials: KC
authors.lastname: Martin
authors.forename: Emily
authors.initials: E
authors.lastname: Resseguie
authors.forename: B Paige
authors.initials: BP
authors.lastname: Lawrence
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002227:Carbazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects*; D009980:Influenza A virus; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D000072317:Polychlorinated Dibenzodioxins / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C111855:6-formylindolo(3,2-b)carbazole; D002227:Carbazoles; D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1
keywords: AhR; FICZ; TCDD; influenza virus.