Induction of Colonic Regulatory T Cells by Mesalamine by Activating the Aryl Hydrocarbon Receptor.
Induction of Colonic Regulatory T Cells by Mesalamine by Activating the Aryl Hydrocarbon Receptor.
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DOI：
10.1016/j.jcmgh.2017.03.010
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发表时间：
2017-07
影响因子：
7.2
通讯作者：
Nakao A
中科院分区：
文献类型：
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作者：
Oh-Oka K;Kojima Y;Uchida K;Yoda K;Ishimaru K;Nakajima S;Hemmi J;Kano H;Fujii-Kuriyama Y;Katoh R;Ito H;Nakao A
美沙拉嗪是治疗炎症性肠病（IBD）的一线药物。然而，其机制尚未完全了解。CD 4 + Foxp 3+调节性T细胞（Treg）在抑制IBD中发挥潜在作用。这项研究确定了美沙拉嗪的抗炎活性是否与结肠中的Treg诱导有关。我们检查了口服美沙拉嗪后野生型小鼠、芳烃受体缺陷小鼠（AhR-/-小鼠）和造血细胞中缺乏AhR的骨髓嵌合小鼠（BM-AhR-/-小鼠）结肠中TcR的频率。我们还检测了美沙拉嗪对结肠中转化生长因子（TGF）-β表达的影响。用美沙拉嗪治疗野生型小鼠增加了结肠中TcR的积累，并上调了AhR靶基因Cyp 1A 1，但在AhR-/-或BM-AhR-/-小鼠中没有观察到这种效应。此外，美沙拉嗪促进幼稚T细胞在体外分化为TcB，伴随着AhR活化。用美沙拉嗪处理的小鼠在结肠中表现出以AhR依赖性方式增加的活性形式的TGF-β水平，并且TGF-β信号传导的阻断抑制了结肠中美沙拉嗪对TGF-β的诱导。此外，用美沙拉嗪预处理的小鼠获得了对葡聚糖硫酸钠诱导的结肠炎的抗性。我们提出了美沙拉嗪治疗结肠炎的一种新的抗炎机制：通过AhR途径诱导结肠中的TcR，然后激活TGF-β。
Mesalamine is a first-line drug for treatment of inflammatory bowel diseases (IBD). However, its mechanisms are not fully understood. CD4+ Foxp3+ regulatory T cells (Tregs) play a potential role in suppressing IBD. This study determined whether the anti-inflammatory activity of mesalamine is related to Treg induction in the colon. We examined the frequencies of Tregs in the colons of wild-type mice, mice deficient for aryl hydrocarbon receptor (AhR-/- mice), and bone marrow–chimeric mice lacking AhR in hematopoietic cells (BM-AhR-/- mice), following oral treatment with mesalamine. We also examined the effects of mesalamine on transforming growth factor (TGF)-β expression in the colon. Treatment of wild-type mice with mesalamine increased the accumulation of Tregs in the colon and up-regulated the AhR target gene Cyp1A1, but this effect was not observed in AhR-/- or BM-AhR-/- mice. In addition, mesalamine promoted in vitro differentiation of naive T cells to Tregs, concomitant with AhR activation. Mice treated with mesalamine exhibited increased levels of the active form of TGF-β in the colon in an AhR-dependent manner and blockade of TGF-β signaling suppressed induction of Tregs by mesalamine in the colon. Furthermore, mice pretreated with mesalamine acquired resistance to dextran sodium sulfate–induced colitis. We propose a novel anti-inflammatory mechanism of mesalamine for colitis: induction of Tregs in the colon via the AhR pathway, followed by TGF-β activation.