title: Non-dioxin-like AhR ligands in a mouse peanut allergy model.
abstract: Recently, we have shown that AhR activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses sensitization to peanut at least in part by inducing a functional shift toward CD4(+)CD25(+)Foxp3(+) T cells. Next to TCDD, numerous other AhR ligands have been described. In this study, we investigated the effect of three structurally different non-dioxin-like AhR ligands, e.g., 6-formylindolo[3,2-b]carbazole (FICZ), β-naphthoflavone (β-NF), and 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF), on peanut sensitization. Female C57BL/6 mice were sensitized by administering peanut extract (PE) by gavage in the presence of cholera toxin. Before and during peanut sensitization, mice were treated with FICZ, β-NF, or 6-MCDF. AhR gene transcription in duodenum and liver was investigated on day 5, even as the effect of these AhR ligands on CD4(+)CD25(+)Foxp3(+) T(reg) cells in spleen and mesenteric lymph nodes (MLNs). Mice treated with TCDD were included as a positive control. Furthermore, the murine reporter cell line H1G1.1c3 (CAFLUX) was used to investigate the possible role of metabolism of TCDD, FICZ, β-NF, and 6-MCDF on AhR activation in vitro. TCDD, but not FICZ, β-NF, and 6-MCDF, suppressed sensitization to peanut (measured by PE-specific IgE, IgG1, IgG2a and PE-induced interleukin (IL)-5, IL-10, IL-13, IL-17a, IL-22, and interferon-γ). In addition, FICZ, β-NF, and 6-MCDF treatments less effectively induced AhR gene transcription (measured by gene expression of AhR, AhRR, CYP1A1, CYP1A2, CYP1B1) compared with TCDD-treated mice. Furthermore, FICZ, β-NF and 6-MCDF did not increase the percentage of CD4(+)CD25(+)Foxp3(+) T(reg) cells in spleen and mesenteric lymph nodes compared with PE-sensitized mice, in contrast to TCDD. Inhibition of metabolism in vitro increased AhR activation. Together, these data shows that TCDD, but not FICZ, β-NF, and 6-MCDF suppresses sensitization to peanut. Differences in metabolism, AhR binding and subsequent gene transcription might explain these findings and warrant further studies to investigate the role of the AhR in food allergic responses.
authors.affiliation: Department of Toxicology, Institute for Risk Assessment Sciences, Utrecht University, 3508 TD Utrecht, The Netherlands.
authors.forename: Veronica J
authors.initials: VJ
authors.lastname: Schulz
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Smit
authors.forename: Veerle
authors.initials: V
authors.lastname: Huijgen
authors.forename: Marianne
authors.initials: M
authors.lastname: Bol-Schoenmakers
authors.forename: Manon
authors.initials: M
authors.lastname: van Roest
authors.forename: Laura J W
authors.initials: LJ
authors.lastname: Kruijssen
authors.forename: Daniëlle
authors.initials: D
authors.lastname: Fiechter
authors.forename: Ine
authors.initials: I
authors.lastname: Hassing
authors.forename: Rob
authors.initials: R
authors.lastname: Bleumink
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
authors.forename: Majorie B M
authors.initials: MB
authors.lastname: van Duursen
authors.forename: Martin
authors.initials: M
authors.lastname: van den Berg
authors.forename: Raymond H H
authors.initials: RH
authors.lastname: Pieters
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D021183:Peanut Hypersensitivity / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon