Bucheon St Mary's Hospital, Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Bucheon City, Gyeonggi-do, Republic of Korea.
Exp Mol Med. 2013 Oct 4;45(10):e46. doi: 10.1038/emm.2013.89.
Interleukin (IL)-27 is a novel cytokine of the IL-6/IL-12 family that has been reported to be involved in the pathogenesis of autoimmune diseases and has a pivotal role as both a pro- and anti-inflammatory cytokine. We investigated the in vivo effects of IL-27 on arthritis severity in a murine collagen-induced arthritis (CIA) model and its mechanism of action regarding control of regulatory T (Tregs) and IL-17-producing T helper 17 (Th17) cells. IL-27-Fc-treated CIA mice showed a lower severity of arthritis. IL-17 expression in the spleens was significantly decreased in IL-27-Fc-treated CIA mice compared with that in the CIA model. The Th17 population was decreased in the spleens of IL-27-Fc-treated CIA mice, whereas the CD4(+)CD25(+)Foxp3(+) Treg population increased. In vitro studies revealed that IL-27 inhibited IL-17 production in murine CD4(+) T cells, and the effect was associated with retinoic acid-related orphan receptor γT and signal transducer and activator of transcription 3 inhibition. In contrast, fluorescein isothiocyanate-labeled forkhead box P3 (Foxp3) and IL-10 were profoundly augmented by IL-27 treatment. Regarding the suppressive capacity of Treg cells, the proportions of CTLA-4(+) (cytotoxic T-lymphocyte antigen 4), PD-1(+) (programmed cell death protein 1) and GITR(+) (glucocorticoid-induced tumor necrosis factor receptor) Tregs increased in the spleens of IL-27-Fc-treated CIA mice. Furthermore, in vitro differentiated Treg cells with IL-27 exerted a more suppressive capacity on T-cell proliferation. We found that IL-27 acts as a reciprocal regulator of the Th17 and Treg populations in CD4(+) cells isolated from healthy human peripheral blood mononuclear cells (PBMCs), as well as from humans with rheumatoid arthritis (RA) PBMCs. Our study suggests that IL-27 has the potential to ameliorate overwhelming inflammation in patients with RA through a reciprocal regulation of Th17 and Treg cells.
白细胞介素 (IL)-27 是一种新型细胞因子，属于 IL-6/IL-12 家族，据报道其参与了自身免疫性疾病的发病机制，并作为一种促炎和抗炎细胞因子发挥关键作用。我们在胶原诱导性关节炎 (CIA) 小鼠模型中研究了 IL-27 对关节炎严重程度的体内影响及其对调节性 T (Treg) 和白细胞介素-17 产生的辅助性 T 细胞 17 (Th17) 细胞的作用机制。IL-27-Fc 治疗的 CIA 小鼠关节炎严重程度较低。与 CIA 模型相比，IL-27-Fc 治疗的 CIA 小鼠脾脏中 IL-17 的表达显著降低。IL-27-Fc 治疗的 CIA 小鼠脾脏中的 Th17 群体减少，而 CD4(+)CD25(+)Foxp3(+)Treg 群体增加。体外研究表明，IL-27 抑制了小鼠 CD4(+)T 细胞中 IL-17 的产生，这种作用与维甲酸相关孤儿受体 γT 和信号转导和转录激活因子 3 的抑制有关。相比之下，IL-27 处理显著增加了荧光素异硫氰酸酯标记的叉头框 P3 (Foxp3) 和 IL-10 的表达。关于 Treg 细胞的抑制能力，IL-27-Fc 治疗的 CIA 小鼠脾脏中 CTLA-4(+)（细胞毒性 T 淋巴细胞抗原 4）、PD-1(+)（程序性细胞死亡蛋白 1）和 GITR(+)（糖皮质激素诱导的肿瘤坏死因子受体）Treg 的比例增加。此外，体外分化的 Treg 细胞在 IL-27 作用下对 T 细胞增殖具有更强的抑制能力。我们发现，IL-27 作为来自健康人外周血单个核细胞 (PBMC) 以及类风湿关节炎 (RA) PBMC 的 CD4(+)细胞中 Th17 和 Treg 群体的相互调节因子发挥作用。我们的研究表明，IL-27 通过对 Th17 和 Treg 细胞的相互调节，有可能改善 RA 患者的过度炎症。
