Cai Z, Wong C K, Dong J, Chu M, Jiao D, Kam N W, Lam C W K, Tam L S
Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong.
Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
Clin Exp Immunol. 2015 Aug;181(2):253-66. doi: 10.1111/cei.12639.
The immunological mechanisms mediated by regulatory cytokine interleukin (IL)-35 are unclear in systemic lupus erythematosus (SLE). We investigated the frequency of CD4(+) CD25(+) forkhead box protein 3 (FoxP3)(+) regulatory T (Treg ) and IL-10(+) regulatory B (Breg ) cells and related immunoregulatory mechanisms in a female Murphy Roths Large (MRL)/lpr mouse model of spontaneous lupus-like disease, with or without IL-35 treatment. A remission of histopathology characteristics of lupus flare and nephritis was observed in the MRL/lpr mice upon IL-35 treatment. Accordingly, IL-35 and IL-35 receptor subunits (gp130 and IL-12Rβ2) and cytokines of MRL/lpr and BALB/c mice (normal controls) were measured. The increased anti-inflammatory cytokines and decreased proinflammatory cytokines were possibly associated with the restoration of Treg and Breg frequency in MRL/lpr mice with IL-35 treatment, compared to phosphate-buffered saline (PBS) treatment. mRNA expressions of Treg -related FoxP3, IL-35 subunit (p35 and EBI3) and soluble IL-35 receptor subunit (gp130 and IL12Rβ2) in splenic cells were up-regulated significantly in IL-35-treated mice. Compared with the PBS treatment group, IL-35-treated MRL/lpr mice showed an up-regulation of Treg -related genes and the activation of IL-35-related intracellular Janus kinase/signal transducer and activator of transcription signal pathways, thereby indicating the immunoregulatory role of IL-35 in SLE. These in vivo findings may provide a biochemical basis for further investigation of the regulatory mechanisms of IL-35 for the treatment of autoimmune-mediated inflammation.
调节性细胞因子白细胞介素（IL）-35介导的免疫机制在系统性红斑狼疮（SLE）中尚不清楚。我们研究了在有或无IL-35治疗的自发性狼疮样疾病雌性墨菲罗斯大鼠（MRL）/lpr小鼠模型中，CD4(+) CD25(+) 叉头框蛋白3（FoxP3）(+) 调节性T（Treg）细胞和IL-10(+) 调节性B（Breg）细胞的频率以及相关免疫调节机制。IL-35治疗后，MRL/lpr小鼠狼疮发作和肾炎的组织病理学特征得到缓解。据此，检测了MRL/lpr和BALB/c小鼠（正常对照）的IL-35及其受体亚基（gp130和IL-12Rβ2）以及细胞因子。与磷酸盐缓冲盐水（PBS）治疗相比，IL-35治疗的MRL/lpr小鼠中抗炎细胞因子增加和促炎细胞因子减少可能与Treg和Breg频率的恢复有关。IL-35治疗的小鼠脾细胞中Treg相关的FoxP3、IL-35亚基（p35和EBI3）以及可溶性IL-35受体亚基（gp130和IL12Rβ2）的mRNA表达显著上调。与PBS治疗组相比，IL-35治疗的MRL/lpr小鼠显示Treg相关基因上调以及IL-35相关细胞内Janus激酶/信号转导和转录激活因子信号通路的激活，从而表明IL-35在SLE中的免疫调节作用。这些体内研究结果可能为进一步研究IL-35治疗自身免疫介导炎症的调节机制提供生化基础。
