Department of Toxicology, Institute for Risk Assessment Sciences, Utrecht University, 3508 TD Utrecht, The Netherlands.
Toxicol Sci. 2012 Jul;128(1):92-102. doi: 10.1093/toxsci/kfs131. Epub 2012 Apr 6.
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.
最近，我们发现 2,3,7,8-四氯二苯并对二恶英（TCDD）通过激活芳香烃受体（AhR）抑制花生致敏作用，其机制至少部分是通过诱导功能性向 CD4+CD25+Foxp3+T 细胞偏移。除了 TCDD 以外，还有许多其他的 AhR 配体已被描述。在这项研究中，我们研究了三种结构不同的非二恶英样 AhR 配体，即 6-甲氧基-1,3,8-三氯二苯并呋喃（6-MCDF）、β-萘黄酮（β-NF）和 6-甲酰基吲哚并[3,2-b]咔唑（FICZ），对花生致敏的影响。雌性 C57BL/6 小鼠通过灌胃给予花生提取物（PE）并同时给予霍乱毒素进行致敏。在花生致敏之前和期间，用 FICZ、β-NF 或 6-MCDF 处理小鼠。在第 5 天检测十二指肠和肝脏中的 AhR 基因转录，同时检测这些 AhR 配体对脾脏和肠系膜淋巴结（MLNs）中 CD4+CD25+Foxp3+Treg 细胞的影响。用 TCDD 处理的小鼠作为阳性对照。此外，使用小鼠报告细胞系 H1G1.1c3（CAFLUX）来研究 TCDD、FICZ、β-NF 和 6-MCDF 在体外激活 AhR 中的可能代谢作用。与 FICZ、β-NF 和 6-MCDF 不同，TCDD 抑制了花生致敏（通过 PE 特异性 IgE、IgG1、IgG2a 和 PE 诱导的白细胞介素（IL）-5、IL-10、IL-13、IL-17a、IL-22 和干扰素-γ来测量）。此外，与 TCDD 处理的小鼠相比，FICZ、β-NF 和 6-MCDF 处理小鼠 AhR 基因转录（通过 AhR、AhRR、CYP1A1、CYP1A2、CYP1B1 的基因表达来测量）的诱导作用较弱。此外，与 PE 致敏的小鼠相比，FICZ、β-NF 和 6-MCDF 处理并未增加脾脏和肠系膜淋巴结中 CD4+CD25+Foxp3+Treg 细胞的百分比，而 TCDD 则会增加。体外代谢抑制增加了 AhR 激活。综上所述，这些数据表明 TCDD 而不是 FICZ、β-NF 和 6-MCDF 抑制了对花生的致敏作用。代谢、AhR 结合和随后的基因转录的差异可能解释了这些发现，并需要进一步的研究来调查 AhR 在食物过敏反应中的作用。
