Zhang Zuofu, Cao Chunni, Sun Shui, Xu Qiang
Department of Joint Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, P.R. China.
Department of Hyperbaric Oxygen, Yantai Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China.
Mol Med Rep. 2015 Aug;12(2):2902-6. doi: 10.3892/mmr.2015.3759. Epub 2015 May 8.
Spleen tyrosine kinase (SYK) has an important role in immunoreceptor signaling, and SYK inhibition has accordingly attenuated immune-mediated injury in several models. Therefore, the present study examined the effect of SYK inhibition with the selective spleen tyrosine kinase inhibitor P505-15 in experimental rheumatoid arthritis (RA) using a murine model of collagen-induced arthritis (CIA). Treatment with the selective SYK inhibitor P505-15, a small molecule kinase inhibitor selective for SYK, led to a reduction in arthritis score and attenuated histological damage. P505-15 reduced cartilage destruction and macrophage infiltration in CIA mice. In addition, P505-15-treated mice showed lower circulating levels of type II-collagen immunoglobulin (Ig)G1 and IgG2 and pro-inflammatory cytokines. Importantly, P505-15 treatment markedly reduced the interleukin 1β-stimulated inflammatory response in human RA synovial cells. Given these encouraging results, a key function for SYK in the development of RA was identified, highlighting that SYK may be a potential therapeutic target for human RA.
脾酪氨酸激酶（SYK）在免疫受体信号传导中起重要作用，因此，在多种模型中，抑制SYK可减轻免疫介导的损伤。因此，本研究使用胶原诱导性关节炎（CIA）小鼠模型，研究了选择性脾酪氨酸激酶抑制剂P505-15抑制SYK对实验性类风湿性关节炎（RA）的影响。用选择性SYK抑制剂P505-15（一种对SYK具有选择性的小分子激酶抑制剂）进行治疗，可使关节炎评分降低，并减轻组织学损伤。P505-15减少了CIA小鼠的软骨破坏和巨噬细胞浸润。此外，经P505-15处理的小鼠循环中的II型胶原免疫球蛋白（Ig）G1和IgG2以及促炎细胞因子水平较低。重要的是，P505-15治疗显著降低了白细胞介素1β刺激的人RA滑膜细胞的炎症反应。鉴于这些令人鼓舞的结果，确定了SYK在RA发病过程中的关键作用，这突出表明SYK可能是人类RA的一个潜在治疗靶点。
