Department of Rheumatology and Immunology, University of Szeged, Szeged, Hungary.
Institute of Pharmaceutical Chemistry and Research Group for Stereochemistry, Hungarian Academy of Sciences, University of Szeged, Szeged, Hungary.
Front Immunol. 2021 Apr 9;12:632513. doi: 10.3389/fimmu.2021.632513. eCollection 2021.
Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease with complex pathogenesis involving a variety of immunological events. Recently, it has been suggested that kynurenic acid (KYNA) might be a potential regulator of inflammatory processes in arthritis. KYNA has a definitive anti-inflammatory and immunosuppressive function. The aim of the present study is to investigate the complex effects of a newly synthesized KYNA analog-SZR72 on the production of tumor necrosis factor-α (TNF-α), tumor necrosis factor-stimulated gene-6 (TSG-6), calprotectin (SA1008/9), SA100 12 (EN-RAGE), and HNP1-3 (defensin-α) in the peripheral blood of patients with RA and the various effects of the disease. Patients with RA ( = 93) were selected based on the DAS28 score, medication, and their rheumatoid factor (RF) status, respectively. Peripheral blood samples from 93 patients with RA and 50 controls were obtained, and activated by heat-inactivated . Parallel samples were pretreated before the activation with the KYNA analog N-(2-N, N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride. Following the incubation period (18 h), the supernatants were tested for TNF-α, TSG-6, calprotectin, S100A12, and HNP1-3 content by ELISA. SZR72 inhibited the production of the following inflammatory mediators: TNF-α, calprotectin, S100A12, and HNP1-3 in whole blood cultures. This effect was observed in each group of patients in various phases of the disease. The basic (control) levels of these mediators were higher in the blood of patients than in healthy donors. In contrast, lower TSG-6 levels were detected in patients with RA compared to healthy controls. In addition, the KYNA analog exerted a stimulatory effect on the TSG-6 production in human whole blood cultures of patients with RA in various phases of the disease. These data further support the immunomodulatory role of KYNA in RA resulting in anti-inflammatory effects and draw the attention to the importance of the synthesis of the KYNA analog, which might have a future therapeutic potential.
类风湿关节炎（RA）是一种慢性炎症性关节疾病，其发病机制复杂，涉及多种免疫事件。最近，有人提出犬尿氨酸（KYNA）可能是关节炎炎症过程的潜在调节剂。KYNA 具有明确的抗炎和免疫抑制作用。本研究旨在探讨新合成的 KYNA 类似物-SZR72 对 RA 患者外周血肿瘤坏死因子-α（TNF-α）、肿瘤坏死因子刺激基因-6（TSG-6）、钙卫蛋白（SA1008/9）、SA10012（EN-RAGE）和 HNP1-3（防御素-α）产生的复杂影响，以及疾病的各种影响。根据 DAS28 评分、药物和类风湿因子（RF）状态，分别选择了 93 名 RA 患者作为研究对象。收集了 93 名 RA 患者和 50 名对照者的外周血样本，用热灭活的进行激活。在激活前，平行样本用 KYNA 类似物 N-（2-N，N-二甲基氨基乙基）-4-氧代-1H-喹啉-2-甲酰胺盐酸盐预处理。孵育期（18 小时）后，通过 ELISA 法检测上清液中 TNF-α、TSG-6、钙卫蛋白、S100A12 和 HNP1-3 的含量。SZR72 抑制了全血培养中以下炎症介质的产生：TNF-α、钙卫蛋白、S100A12 和 HNP1-3。在疾病的各个阶段，每组患者均观察到这种作用。这些介质的基础（对照）水平在患者血液中高于健康供体。相比之下，RA 患者的 TSG-6 水平较低。此外，KYNA 类似物在 RA 患者各期的全血培养中对 TSG-6 的产生有刺激作用。这些数据进一步支持 KYNA 在 RA 中的免疫调节作用，导致抗炎作用，并引起人们对 KYNA 类似物合成的重要性的关注，这可能具有未来的治疗潜力。
