Liao Jiongbo, Wang Xiao, Bi Yujing, Shen Bo, Shao Kun, Yang Hui, Lu Yun, Zhang Zhengguo, Chen Xi, Liu Huanrong, Wang Jian, Chu Yiwei, Xue Lixiang, Wang Xianghui, Liu Guangwei
Ruijin Hospital and Medical School of Shanghai Jiao Tong University, Shanghai, China; Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, and Biotherapy Research Center, Institute of Immunobiology, and.
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, and Biotherapy Research Center, Institute of Immunobiology, and.
J Leukoc Biol. 2014 Nov;96(5):675-84. doi: 10.1189/jlb.2HI1113-611RR. Epub 2014 Jun 19.
Whereas GCs have been demonstrated to be beneficial for transplantation patients, the pharmacological mechanisms remain unknown. Herein, the role of GR signaling was investigated via a pharmacological approach in a murine allogeneic skin transplantation model. The GC Dex, a representative GC, significantly relieved allograft rejection. In Dex-treated allograft recipient mice, CD11b(+)Gr1(+) MDSCs prolonged graft survival and acted as functional suppressive immune modulators that resulted in fewer IFN-γ-producing Th1 cells and a greater number of IL-4-producing Th2 cells. In agreement, Dex-treated MDSCs promoted reciprocal differentiation between Th1 and Th2 in vivo. Importantly, the GR is required in the Dex-induced MDSC effects. The blocking of GR with RU486 significantly diminished the expression of CXCR2 and the recruitment of CD11b(+)Gr1(+) MDSCs, thereby recovering the increased MDSC-suppressive activity induced by Dex. Mechanistically, Dex treatment induced MDSC iNOS expression and NO production. Pharmacologic inhibition of iNOS completely eliminated the MDSC-suppressive function and the effects on T cell differentiation. This study shows MDSCs to be an essential component in the prolongation of allograft survival following Dex or RU486 treatment, validating the GC-GR-NO signaling axis as a potential therapeutic target in transplantation.
尽管糖皮质激素（GCs）已被证明对移植患者有益，但其药理机制仍不清楚。在此，通过药理学方法在小鼠同种异体皮肤移植模型中研究了糖皮质激素受体（GR）信号传导的作用。代表性的糖皮质激素地塞米松（Dex）显著缓解了同种异体移植排斥反应。在接受Dex治疗的同种异体移植受体小鼠中，CD11b(+)Gr1(+)髓系来源的抑制细胞（MDSCs）延长了移植物存活时间，并作为功能性抑制性免疫调节剂发挥作用，导致产生干扰素-γ（IFN-γ）的辅助性T细胞1（Th1细胞）数量减少，而产生白细胞介素-4（IL-4）的辅助性T细胞2（Th2细胞）数量增加。同样，经Dex处理的MDSCs在体内促进了Th1和Th2之间的相互分化。重要的是，GR是Dex诱导的MDSC效应所必需的。用米非司酮（RU486）阻断GR可显著降低CXC趋化因子受体2（CXCR2）的表达以及CD11b(+)Gr1(+)MDSCs的募集，从而恢复由Dex诱导增加的MDSC抑制活性。从机制上讲，Dex处理可诱导MDSC中诱导型一氧化氮合酶（iNOS）的表达和一氧化氮（NO）的产生。对iNOS的药理抑制完全消除了MDSC的抑制功能以及对T细胞分化的影响。本研究表明，MDSCs是Dex或RU486治疗后延长同种异体移植存活时间的重要组成部分，证实了GC-GR-NO信号轴作为移植中潜在治疗靶点的作用。
