Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Japan.
Immunol Lett. 2010 Nov 30;134(1):7-16. doi: 10.1016/j.imlet.2010.07.002. Epub 2010 Jul 23.
1α,25-Dihydroxyvitamin D(3) (1,25D3), the active form of vitamin D(3), is an immunoregulatory hormone with beneficial effects on Th1 cell-mediated inflammatory diseases. Although IL-17-producing CD4(+) T helper (Th17) cells have been recently identified as novel effector cells, the immunomodulating effects of 1,25D3 on Th17 cells have not been well defined. We confirmed here that 1,25D3 inhibited the generation of Th17 cells in vitro. Interestingly, 1,25D3 synergistically suppressed the generation of Th17 cells by the combination with all-trans retinoic acid (ATRA). 1,25D3 and ATRA suppressed the development of allergen-induced contact hypersensitivity (CHS) in a mouse ear swelling model. In addition, we found that 1,25D3 and ATRA significantly inhibited the development of human Th17 cells from both naïve and memory human CD4(+) T cells. 1,25D3 and ATRA effectively suppressed mRNA expressions of IL-1R1, IL-21R, IL-23R, RORC, and AHR in human T cells. ATRA further suppressed IL-6R, whereas 1,25D3 did not. Finally, we found that 1,25D3 and ATRA remarkably blocked IL-22 as well as IL-17 mRNA expression in human memory CD4(+) T cells. Thus, we initially reveal that 1,25D3 and ATRA have synergistic effects on the generation of Th17 cells, suggesting that the combination with ATRA would provide a promising novel therapy for Th17 cell-related immune diseases including skin inflammation.
1α,25-二羟维生素 D(3)（1,25D3）是维生素 D(3)的活性形式，是一种具有免疫调节作用的激素，对 Th1 细胞介导的炎症性疾病有有益的影响。虽然最近已经确定了产生 IL-17 的 CD4(+)T 辅助（Th17）细胞是新型效应细胞，但 1,25D3 对 Th17 细胞的免疫调节作用尚未得到很好的定义。我们在这里证实，1,25D3 可抑制体外 Th17 细胞的生成。有趣的是，1,25D3 与全反式视黄酸（ATRA）联合使用可协同抑制 Th17 细胞的生成。1,25D3 和 ATRA 在小鼠耳肿胀模型中抑制变应原诱导的接触超敏反应（CHS）的发展。此外，我们发现 1,25D3 和 ATRA 可显著抑制从幼稚和记忆人类 CD4(+)T 细胞中产生的人类 Th17 细胞的发育。1,25D3 和 ATRA 可有效抑制人类 T 细胞中 IL-1R1、IL-21R、IL-23R、RORC 和 AHR 的 mRNA 表达。ATRA 进一步抑制了 IL-6R，而 1,25D3 则没有。最后，我们发现 1,25D3 和 ATRA 可显著阻断人类记忆 CD4(+)T 细胞中 IL-22 以及 IL-17 的 mRNA 表达。因此，我们初步揭示 1,25D3 和 ATRA 对 Th17 细胞的生成具有协同作用，表明与 ATRA 联合使用可能为包括皮肤炎症在内的 Th17 细胞相关免疫疾病提供一种有前途的新疗法。
