Cell-penetrable mouse forkhead box protein 3 alleviates experimental arthritis in mice by up-regulating regulatory T cells
Cell-penetrable mouse forkhead box protein 3 alleviates experimental arthritis in mice by up-regulating regulatory T cells
复制标题
细胞可穿透的小鼠叉头盒蛋白 3 通过上调调节性 T 细胞来减轻小鼠的实验性关节炎。
DOI：
10.1111/cei.12630
复制
发表时间：
2015-07-01
影响因子：
4.6
通讯作者：
Shao, Qixiang
中科院分区：
文献类型：
--
作者：
Liu, Xia;Ji, Baoju;Shao, Qixiang
调节性T细胞在自身免疫性疾病和移植排斥反应等临床疾病治疗中具有潜在的应用价值。然而，他们的人数有限。叉头盒蛋白3（FoxP 3）是控制T-reg发育和功能的关键转录因子。在这里，我们产生了一个细胞可渗透的融合蛋白，蛋白转导结构域（PTD）缀合的小鼠FoxP 3蛋白（PTD-mFoxP 3），并评估PTD-mFoxp 3是否可以减轻类风湿性关节炎（RA）的胶原诱导的关节炎（CIA）小鼠模型。结果表明，PTD-mFoxP 3能有效地转导入细胞，抑制T细胞活化，抑制细胞增殖。在活化的CD 4（+）CD 25（-）T细胞中，它降低了白细胞介素（IL）2和干扰素（IFN）的表达，并增加了IL-10的表达。PTD-mFoxP 3转导的CD 4（+）CD 25（-）T细胞减弱活化的CD 4（+）CD 25（-）T细胞的增殖。此外，PTD-mFoxP 3在体外阻断了Th 17分化程序，并通过调节类维生素A相关孤儿受体γ t（RORt）的诱导和水平下调了T细胞的IL-17产生。关节内递送PTD-mFoxP 3显著延迟了CIA小鼠的疾病发病率并减轻了CIA小鼠的自身免疫症状。此外，PTD-mFoxP 3的保护作用与调节辅助性T细胞17型（Th 17）和T-Th的平衡有关。这些结果表明PTD-mFoxP 3可能是RA治疗的候选药物。
Regulatory T cells (T-regs) have potential applications in clinical disease therapy, such as autoimmune diseases and transplant rejection. However, their numbers are limited. Forkhead box protein 3 (FoxP3) is a key transcription factor that controls T-reg development and function. Here, we generated a cell-permeable fusion protein, protein transduction domain (PTD)-conjugated mouse FoxP3 protein (PTD-mFoxP3), and evaluated whether PTD-mFoxp3 can alleviate rheumatoid arthritis (RA) in the collagen-induced arthritis (CIA) mouse model. As expected, PTD-mFoxP3 was transduced into cells effectively, and inhibited T cell activation and attenuated the cell proliferation. It decreased interleukin (IL) 2 and interferon (IFN)- expression, and increased IL-10 expression in activated CD4(+)CD25(-) T cells. PTD-mFoxP3-transduced CD4(+)CD25(-) T cells attenuated proliferation of activated CD4(+)CD25(-) T cells. In addition, PTD-mFoxP3 blocked the Th17 differentiation programme in vitro and down-regulated IL-17 production from T cells by modulating induction and levels of retinoid-related orphan receptor gamma t (RORt). Intra-articular delivery of PTD-mFoxP3 delayed disease incidence remarkably and alleviated autoimmune symptoms of CIA mice. Moreover, protective effects of PTD-mFoxP3 were associated with regulating the balance of T helper type 17 (Th17) and T-regs. These results suggest that PTD-mFoxP3 may be a candidate for RA therapy.