Patients with rheumatoid arthritis (RA) have increased levels of interleukin-18 (IL-18) and decreased levels of IL-18 binding protein (IL-18BP) in the serum and synovial fluid (SF) compared to those in patients with osteoarthritis (OA) or in healthy controls. In this study, we evaluated the effects of IL-18BP on osteoclastogenesis and T cell differentiation in RA in vitro. Serum and SF of patients with RA and OA were collected to compare IL-18 and IL-18BP levels by the enzyme-linked immunosorbent assay. Peripheral blood mononuclear cells (PBMCs) and SF mononuclear cells (SFMCs) of RA patients were cultured under type 17 helper T cell (Th17) polarisation conditions with or without IL-18BP. In addition, PBMCs were cultured in the presence of receptor activator of nuclear factor kappa-Β ligand (RANKL) or IL-17A with or without IL-18BP, and tartrate-resistant acid phosphatase (TRAP) staining and real-time quantitative polymerase chain reaction for expression levels of osteoclast-related genes were performed. IL-18 levels were higher in the serum and SF of patients with RA, whereas IL-18BP was lower in the SF of patients with RA than in the control group. Treatment of patients’ PBMCs with IL-18BP decreased the differentiation of CD4+ IL-17A+ and CD4+ RANKL+ T cells, whereas the differentiation of CD4+CD25highFOXP3+ T cell population increased in a dose-dependent manner. These changes in CD4+ T cell differentiation were also observed in the SFMCs of patients with RA. The levels IL-17A and soluble RANKL in the culture medium were significantly decreased by IL-18BP. IL-18BP administration decreased TRAP+ cell counts in a dose-dependent manner on the background of stimulation with RANKL-and IL-17A. In addition, expression levels of TRAP, NFATC1, CTSK, and TNFRSF11A (RANK) genes were lower in the IL-18BP treated cells. We showed that IL-18BP can rectify the Th17/Treg imbalance and decrease IL-17-induced osteoclastogenesis in PBMCs from patients with RA. Therefore, IL-18BP may have therapeutic potential for RA treatment.

中文翻译：

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IL-18 结合蛋白抑制 IL-17 诱导的破骨细胞生成并纠正类风湿性关节炎中的 17 型辅助性 T 细胞/调节性 T 细胞失衡

与骨关节炎患者相比，类风湿性关节炎 (RA) 患者血清和滑液 (SF) 中白细胞介素 18 (IL-18) 水平升高，IL-18 结合蛋白 (IL-18BP) 水平降低。 OA) 或健康对照。在本研究中，我们评估了 IL-18BP 在体外对 RA 破骨细胞生成和 T 细胞分化的影响。收集 RA 和 OA 患者的血清和 SF，通过酶联免疫吸附试验比较 IL-18 和 IL-18BP 水平。RA 患者的外周血单个核细胞 (PBMC) 和 SF 单个核细胞 (SFMC) 在 17 型辅助 T 细胞 (Th17) 极化条件下培养，有或没有 IL-18BP。此外，PBMCs 在核因子 kappa-Β 配体 (RANKL) 或 IL-17A 的受体激活剂存在下培养，有或没有 IL-18BP，并对破骨细胞相关基因的表达水平进行抗酒石酸酸性磷酸酶（TRAP）染色和实时定量聚合酶链反应。RA患者血清和SF中IL-18水平较高，而RA患者SF中IL-18BP水平低于对照组。用 IL-18BP 治疗患者的 PBMC 可降低 CD4+ IL-17A+ 和 CD4+ RANKL+ T 细胞的分化，而 CD4+CD25highFOXP3+ T 细胞群的分化以剂量依赖性方式增加。在 RA 患者的 SFMC 中也观察到这些 CD4+ T 细胞分化的变化。IL-18BP显着降低了培养基中IL-17A和可溶性RANKL的水平。在 RANKL-和 IL-17A 刺激的背景下，IL-18BP 给药以剂量依赖性方式降低了 TRAP+ 细胞计数。此外，在 IL-18BP 处理的细胞中，TRAP、NFATC1、CTSK 和 TNFRSF11A (RANK) 基因的表达水平较低。我们发现 IL-18BP 可以纠正 RA 患者 PBMC 中的 Th17/Treg 失衡并减少 IL-17 诱导的破骨细胞生成。因此，IL-18BP 可能具有治疗 RA 的潜力。