Retinoic Acid Contributes to the Induction of IL-12-Hypoproducing Dendritic Cells
Retinoic Acid Contributes to the Induction of IL-12-Hypoproducing Dendritic Cells
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DOI：
10.1002/ibd.20934
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发表时间：
2009-10-01
影响因子：
4.9
通讯作者：
Hibi, Toshifumi
中科院分区：
文献类型：
--
作者：
Wada, Yasuyo;Hisamatsu, Tadakazu;Hibi, Toshifumi
背景：维生素 A 是人体免疫系统的重要调节剂，尤其是肠道免疫系统。最近的研究表明，肠道相关树突状细胞 (DC) 中的视黄酸 (RA) 可以增强转化生长因子 (TGF) β 依赖性的幼稚 T 细胞向调节性 T (Treg) 细胞的转化。因此，DC 产生的 RA 有助于肠道内的免疫耐受机制。本研究重点关注RA对DC分化的影响，并试图阐明RA诱导的DC在小鼠结肠炎模型中的作用。方法：用粒细胞-巨噬细胞集落刺激因子和白细胞介素（IL）-4培养人外周血CD14（+）单核细胞，添加或不添加合成RA、Am80。将用Am80培养的分化DC（Am-DC）与传统单核细胞来源的DC（cDC）进行比较。结果：Am-DC表现出巨噬细胞（M phi）样贴壁表型，并且缺乏典型DC标志物CD1a的表达。 Am-DC 产生较少的 IL-12p70，并且通过与初始 T 细胞的同种异体混合淋巴细胞反应显示出对 1 型辅助 T 细胞 (Th1) 的极化能力较低。此外。 Am80 治疗可改善右旋糖酐硫酸钠诱导的小鼠结肠炎的宏观和微观损伤，并抑制结肠炎诱导的肠固有层 IL-12 升高。结论：RA 可能通过局部产生 IL-12 低生产力 DC，在肠道免疫耐受中发挥重要作用。 RA 可能是治疗 Th1 介导的炎症性疾病的有效临床方法，尤其是肠道中发生的克罗恩病等炎症性疾病。
Background: Vitamin A is an important regulator of the human immune system, especially in the gut. Recent studies have revealed that retinoic acid (RA) in gut-associated dendritic cells (DCs) enhances the transforming growth factor (TGF)-beta-dependent conversion of naive T cells into regulatory T (Treg) cells. Thus, RA produced by DCs contributes to immune tolerance mechanisms in the gut. In the present study we focused on the effect of RA on the differentiation of the DC, and tried to clarify the role of DCs induced by RA in a murine colitis model.Methods: Human peripheral blood CD14(+) monocytes were cultured with granulocyte-macrophage colony stimulation factor and interleukin (IL)-4, with or without synthetic RA, Am80. Differentiated DCs cultured with Am80 (Am-DCs) were compared with conventional monocyte-derived DCs (cDCs).Results: Am-DCs showed macrophage (M phi)-like adherent phenotypes, and lacked the expression of the typical DC marker CD1a. Am-DCs produced less IL-12p70 and revealed less polarizing ability toward type 1 helper T cells (Th1) by allogeneic mixed lymphocyte reaction with naive T cells. In addition. Am80 treatment ameliorated macro- and microscopic damage in dextran sodium sulfate-induced colitis in mice, and suppressed the colitis-induced elevation of IL-12 in the intestinal lamina propria.Conclusions: RA might play an important role in gut immune tolerances via local generation of IL-12 hypoproductive DCs. RA may be a useful clinical treatment for Th1-mediated inflammatory diseases, especially those such as Crohn's disease occurring in the gut.