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.

Endogenous ligands of the aryl hydrocarbon receptor regulate lung dendritic cell function

“…43 Similarly, two novel antiallergy therapeutics with AhR binding activity suppressed T-cell activation by DCs in mouse models of allergic airways inflammation, 36,44,45 but several non-dioxin AhR ligands failed to inhibit peanut-specific responses in a food allergy model. 26 The relative contribution of AhR ligands to immune regulation via T cells or DCs is also difficult to assess in whole animal models. Herein, we have shown that endogenous AhR ligands contributed to the regulation of lung immune responses via lung DCs, such that AhR À/À DCs, unable to respond to these ligands, exhibited a pro-inflammatory and pro-allergic phenotype.…”

“…[22][23][24][25] Interestingly, three different non-dioxin AhR ligands all failed to suppress the allergic response in a mouse model of peanut allergy. 26 As a result, the role of endogenous AhR ligands on immune cell function remains unclear. …”

Comparison of Intake and Systemic Relative Effect Potencies of Dioxin-like Compounds in Female Mice after a Single Oral Dose

“…We determined hepatic CYP1A1 activity using ethoxyresorufin- O -deethylase (EROD) activity in hepatic microsomal fractions as described by Schulz et al (2012).…”

Janus-faced Acrolein prevents allergy but accelerates tumor growth by promoting immunoregulatory Foxp3+ cells: Mouse model for passive respiratory exposure

“…Acrolein is known to block NF-κB signaling similar like its chemical derivative cinnamaldehyde29 via its reactive unsaturated aldehyde by preventing oligomerization of TLR4 on the plasma membrane59. Consequently, we went in search for a possible cytosolic interaction partner for acrolein and found AhR that –with other ligands - has already been associated with suppression of Th2 cell differentiation6061 and increased numbers of CD4+CD25+Foxp3+ cells61 in vivo . Using an AhR- reporter cell line30, we were able to show that acrolein concentration-dependently activated AhR and that activation was antagonised by resveratrol, as well as by the Ahr antagonist 3′-methoxy-4′-nitroflavone.…”