INSERM, UMR 957, Equipe Labellisée LIGUE 2012, Nantes, France.
Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Faculté de Médecine, Nantes, France.
Ann Rheum Dis. 2017 Jul;76(7):1304-1312. doi: 10.1136/annrheumdis-2016-210630. Epub 2017 Mar 13.
Interleukin (IL)-38 is a newly characterised cytokine that belongs to the IL-1 family. This cytokine is expressed in the rheumatoid arthritis (RA) synovial tissue and IL-38 deficient mice have exacerbated arthritis. Here, we analysed the effect of IL-38 overexpression in the joints of arthritic mice, in human macrophages and synovial fibroblasts in vitro.
Articular injections of an adeno-associated virus (AAV) 2/8 encoding IL-38 were performed in collagen-induced arthritis (CIA), K/BxN serum transfer-induced arthritis (STIA) and antigen-induced arthritis (AIA) in mice. The effect of IL-38 overexpression was evaluated through clinical scores, immunohistochemistry, microCT, Luminex and RT-qPCR analysis. THP-1 macrophages were transduced with a lentiviral vector to overexpress IL-38.
Clinical inflammatory scores were significantly decreased after AAV IL-38 injection in joints of mice with CIA and STIA, but not AIA. This decrease was accompanied by reduced macrophage infiltration and a decreased expression of Th17 cytokines (IL-17, IL-23, IL-22) and TNFα. However, IL-38 overexpression had no effect on cartilage or bone destruction. In vitro, the THP-1 monocytic cell line expressed less IL-6, TNFα and IL-23 after IL-38 overexpression. Conditioned media from these cells, containing released IL-38, also exert an anti-inflammatory effect on human primary macrophages and synovial fibroblasts from patients with RA.
This study shows for the first time that IL-38 overexpression attenuates the severity of experimental arthritis. IL-38 may exert its anti-inflammatory effects by decreasing the production of proinflammatory cytokines by macrophages and synovial fibroblasts. This effect can lead to the development of novel treatment strategies in arthritis.
白细胞介素 (IL)-38 是一种新鉴定的细胞因子，属于 IL-1 家族。这种细胞因子在类风湿关节炎 (RA) 滑膜组织中表达，IL-38 缺陷小鼠的关节炎加重。在这里，我们分析了在关节炎小鼠的关节中过表达 IL-38、体外人巨噬细胞和滑膜成纤维细胞中的效果。
在胶原诱导性关节炎 (CIA)、K/BxN 血清转移诱导性关节炎 (STIA) 和抗原诱导性关节炎 (AIA) 小鼠中进行了腺相关病毒 (AAV) 2/8 编码 IL-38 的关节内注射。通过临床评分、免疫组织化学、微 CT、Luminex 和 RT-qPCR 分析评估 IL-38 过表达的效果。用慢病毒载体转导 THP-1 巨噬细胞以过表达 IL-38。
在 CIA 和 STIA 小鼠的关节中注射 AAV IL-38 后，临床炎症评分显著降低，但在 AIA 中没有降低。这种减少伴随着巨噬细胞浸润减少和 Th17 细胞因子（IL-17、IL-23、IL-22）和 TNFα 的表达减少。然而，IL-38 过表达对软骨或骨破坏没有影响。在体外，THP-1 单核细胞系在过表达 IL-38 后表达的 IL-6、TNFα 和 IL-23 减少。含有释放的 IL-38 的这些细胞的条件培养基也对来自 RA 患者的人原代巨噬细胞和滑膜成纤维细胞发挥抗炎作用。
本研究首次表明，IL-38 过表达可减轻实验性关节炎的严重程度。IL-38 可能通过减少巨噬细胞和滑膜成纤维细胞产生促炎细胞因子来发挥其抗炎作用。这种作用可能导致关节炎的新治疗策略的发展。
