Effects of aryl hydrocarbon receptor signaling on the modulation of Th1/Th2 balance
Effects of aryl hydrocarbon receptor signaling on the modulation of Th1/Th2 balance
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DOI：
10.4049/jimmunol.175.11.7348
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发表时间：
2005-12-01
影响因子：
4.4
通讯作者：
Furusako, S
中科院分区：
文献类型：
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作者：
Negishi, T;Kato, Y;Furusako, S
口服活性抗过敏药 M50367 通过抑制体外 Th 细胞分化为 Th2 细胞，使 Th1/Th2 平衡偏向 Th1 优势。给药导致体内 IgE 合成和腹膜嗜酸性粒细胞增多的抑制。在本报告中，我们确定 M50354（M50367 的活性代谢物）是芳烃受体 (AhR) 的配体；该化合物对体外幼稚 Th 细胞分化为 Th1/Th2 以及体内 Th1/Th2 平衡的免疫学作用是通过与 AhR 结合来体现的。这些效应在 AhR 缺陷小鼠中完全消失。 TCR 和 CD28 的共刺激显着上调初始 Th 细胞中的 AhR 表达。通过 M50354 与 AhR 结合抑制幼稚 Th 细胞分化为 Th2 细胞与抑制 Th 细胞中 GATA-3 表达相关。此外，强制表达AhR的组成型活性形式或通过添加代表性配体来激活AhR可抑制幼稚Th细胞分化为Th2细胞。基于这些结果，我们得出结论，AhR 通过激活初始 Th 细胞发挥体内 Th1/Th2 平衡调节剂的作用。
An orally active antiallergic agent, M50367, skews the Th1/Th2 balance toward Th1 dominance by suppressing naive Th cell differentiation into Th2 cells in vitro. Administration results in the suppression of IgE synthesis and peritoneal eosinophilia in vivo. In this report, we determined that M50354 (an active metabolite of M50367) was a ligand for the aryl hydrocarbon receptor (AhR); the immunological effects of this compound on in vitro Th1/Th2 differentiation from naive Th cells and Th1/Th2 balance in vivo were manifested through binding to AhR. These effects were completely abolished in AhR-deficient mice. AhR expression in the naive Th cell was significantly up-regulated by costimulation of TCR and CD28. Suppression of naive Th cell differentiation into Th2 cells via binding of M50354 to AhR was associated with inhibition of GATA-3 expression in Th cells. In addition, forced expression of a constitutively active form of AhR or activation of AhR by the addition of representative ligands suppressed naive Th cell differentiation into Th2 cells. Based on these results, we conclude that AhR functions as a modulator of the in vivo Th1/Th2 balance through activation in naive Th cells.