Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
Department of Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo 11562, Egypt.
Cells. 2019 Aug 3;8(8):823. doi: 10.3390/cells8080823.
Rheumatoid arthritis (RA) is a disease of the joints that causes decreased quality of life. Mesenchymal stromal cells (MSCs) have immunosuppressive properties, with possible use in the treatment of RA. Similarly, interleukin (IL)-4 has been shown as a potential RA treatment. However, their combination has not been explored before. Therefore, this study aimed to investigate the effect of a combination therapy of MSCs and IL-4 in the treatment of RA, using a murine collagen-induced arthritis (CIA) model. Arthritis was induced in Balb/c mice by two intradermal injections of type II collagen (CII), at days 0 and 21. CIA mice were randomly assigned to four groups; group I received an intravenous injection of mouse bone marrow-derived MSCs, while group II received an intraperitoneal injection of IL-4. Group III received a combined treatment of MSC and IL-4, while group IV served as a CIA diseased control group receiving phosphate buffer saline (PBS). A fifth group of healthy mice served as the normal healthy control. To assess changes induced by different treatments, levels of RA-associated inflammatory cytokines and biomarkers were measured in the serum, knee joints, and synovial tissue, using ELISA and Real Time-qPCR. Histopathological features of knee joints were analyzed for all groups. Results showed that combined MSC and IL-4 treatment alleviated signs of synovitis in CIA mice, reverting to the values of healthy controls. This was evident by the decrease in the levels of rheumatic factor (RF), C-reactive protein (CRP) and anti-nuclear antibodies (ANA) by 64, 80, and 71%, respectively, compared to the diseased group. Moreover, tumor necrosis factor-alpha (TNF- α) and monocyte chemoattractant protein-1 (MCP-1) levels decreased by 63 and 68%, respectively. Similarly, our gene expression data showed improvement in mice receiving combined therapy compared to other groups receiving single treatment, where cartilage oligomeric matrix protein (Comp), tissue inhibitor metalloproteinase-1 (Timp1), matrix metalloproteinase1 (Mmp-1), and IL-1 receptor (Il-1r) gene expression levels decreased by 75, 70, and 78%, respectively. Collectively, treatment with a combined therapy of MSC and IL-4 might have an efficient therapeutic effect on arthritis. Thus, further studies are needed to assess the potential of different MSC populations in conjugation with IL-4 in the treatment of experimental arthritis.
类风湿关节炎（RA）是一种关节疾病，会降低生活质量。间充质基质细胞（MSCs）具有免疫抑制特性，可能用于 RA 的治疗。同样，白细胞介素（IL）-4 已被证明是 RA 的一种潜在治疗方法。然而，它们的组合以前尚未被探索过。因此，本研究旨在使用小鼠胶原诱导性关节炎（CIA）模型，研究 MSC 和 IL-4 联合治疗对 RA 的治疗效果。通过两次皮内注射 II 型胶原（CII）在 Balb/c 小鼠中诱导关节炎，在第 0 天和第 21 天。CIA 小鼠被随机分为四组；第一组接受静脉注射鼠骨髓来源的 MSCs，第二组接受腹腔注射 IL-4。第三组接受 MSC 和 IL-4 的联合治疗，第四组作为接受磷酸盐缓冲盐水（PBS）的 CIA 患病对照组。第五组健康小鼠作为正常健康对照组。为了评估不同治疗方法引起的变化，使用 ELISA 和 Real Time-qPCR 测量血清、膝关节和滑膜组织中与 RA 相关的炎症细胞因子和生物标志物的水平。对所有组的膝关节组织学特征进行了分析。结果表明，MSC 和 IL-4 的联合治疗减轻了 CIA 小鼠的滑膜炎迹象，使其恢复到健康对照组的水平。这一点通过风湿因子（RF）、C 反应蛋白（CRP）和抗核抗体（ANA）的水平分别降低 64%、80%和 71%来证明，与患病组相比。此外，肿瘤坏死因子-α（TNF-α）和单核细胞趋化蛋白-1（MCP-1）水平分别降低了 63%和 68%。同样，我们的基因表达数据表明，与接受单一治疗的其他组相比，接受联合治疗的小鼠有所改善，其中软骨寡聚基质蛋白（Comp）、组织抑制剂金属蛋白酶 1（Timp1）、基质金属蛋白酶 1（Mmp-1）和白细胞介素 1 受体（Il-1r）基因表达水平分别降低了 75%、70%和 78%。综上所述，MSC 和 IL-4 的联合治疗可能对关节炎具有有效的治疗效果。因此，需要进一步研究不同 MSC 群体与 IL-4 联合治疗实验性关节炎的潜力。
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