Zhang Zhaozhen, Ma Xiaoran, Zha Zhuqing, Zhao Zhiwei, Li Jitian
Department of Bone Surgery, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, 100 Yongping Road, Henan Province, Zhengzhou City, 450000, China.
Department of Bone Surgery, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, 100 Yongping Road, Henan Province, Zhengzhou City, 450000, China.
Mol Immunol. 2022 Jan;141:53-59. doi: 10.1016/j.molimm.2021.10.020. Epub 2021 Nov 19.
Rheumatoid arthritis (RA) is a common autoimmune disease in the elderly and it has been recently reported to be significantly associated with the activation of mast cells in joint tissues. IL-17A is a vital mediator that stimulates the activation of inflammation. Allopurinol is a classic agent for the suppression of uric acid production, recently reported to exert therapeutic effects on RA. In the present study, we investigated the regulatory effect of allopurinol against IL-17A-induced inflammatory response in mast cells and explored the potential mechanism of allopurinol on RA treatment. Firstly, we found that compared to normal synovium, IL-17A was significantly upregulated in the human RA synovium. IL-17A was used to stimulate an inflammatory state in mast cells in the absence or presence of allopurinol. We found that the production of inflammatory factors, PGE, and COX-2 was significantly elevated in IL-17A-treated mast cells, accompanied by the activation of the iNOS/NO axis and the elevated secretion of ROS. After treatment with allopurinol, the elevated inflammation, activated COX-2/PGE and iNOS/NO axis, and oxidative stress were all dramatically alleviated. Mechanistically, the activated JNK/AP-1 and NF-κB pathways in IL-17A-treated mast cells were dramatically suppressed by the introduction of allopurinol. Taken together, our data reveal that allopurinol significantly alleviated the IL-17A-induced inflammatory response in mast cells.
类风湿关节炎（RA）是老年人常见的自身免疫性疾病，最近有报道称其与关节组织中肥大细胞的激活显著相关。白细胞介素-17A（IL-17A）是刺激炎症激活的重要介质。别嘌醇是一种抑制尿酸生成的经典药物，最近报道其对RA有治疗作用。在本研究中，我们研究了别嘌醇对IL-17A诱导的肥大细胞炎症反应的调节作用，并探讨了别嘌醇治疗RA的潜在机制。首先，我们发现与正常滑膜相比，IL-17A在人类RA滑膜中显著上调。在有或没有别嘌醇的情况下，用IL-17A刺激肥大细胞进入炎症状态。我们发现，在经IL-17A处理的肥大细胞中，炎症因子、前列腺素E（PGE）和环氧化酶-2（COX-2）的产生显著升高，同时诱导型一氧化氮合酶/一氧化氮（iNOS/NO）轴激活，活性氧（ROS）分泌增加。用别嘌醇处理后，炎症升高、COX-2/PGE和iNOS/NO轴激活以及氧化应激均得到显著缓解。机制上，别嘌醇可显著抑制经IL-17A处理的肥大细胞中激活的JNK/AP-1和核因子κB（NF-κB）信号通路。综上所述，我们的数据表明别嘌醇可显著减轻IL-17A诱导的肥大细胞炎症反应。
