Phospholipase D1 (PLD1), which catalyzes the hydrolysis of phosphatidylcholine to phosphatidic acid and choline, plays multiple roles in inflammation. We investigated the therapeutic effects of the newly developed PLD1 inhibitors A2998, A3000, and A3773 in vitro and in vivo rheumatoid arthritis (RA) model. A3373 reduced the levels of LPS-induced TNF-α, IL-6, and IgG in murine splenocytes in vitro. A3373 also decreased the levels of IFN-γ and IL-17 and the frequencies of Th1, Th17 cells and germinal-center B cells, in splenocytes in vitro. A3373 ameliorated the severity of collagen-induced arthritis (CIA) and suppressed infiltration of inflammatory cells into the joint tissues of mice with CIA compared with vehicle-treated mice. Moreover, A3373 prevented systemic bone demineralization in mice with CIA and suppressed osteoclast differentiation and the mRNA levels of osteoclastogenesis markers in vitro. These results suggest that A3373 has therapeutic potential for RA.

磷脂酶 D1 (PLD1) 可催化磷脂酰胆碱水解为磷脂酸和胆碱，在炎症中发挥多种作用。我们研究了新开发的 PLD1 抑制剂 A2998、A3000 和 A3773体外和体内类风湿性关节炎 (RA) 模型的治疗效果。A3373在体外降低小鼠脾细胞中 LPS 诱导的 TNF-α、IL-6 和 IgG 水平。在体外，A3373 还降低了脾细胞中 IFN-γ 和 IL-17 的水平以及 Th1、Th17 细胞和生发中心 B 细胞的频率。与媒介物治疗的小鼠相比，A3373 改善了胶原诱导的关节炎 (CIA) 的严重程度，并抑制了 CIA 小鼠关节组织中炎症细胞的浸润。此外，A3373 可以防止 CIA 小鼠的全身骨脱矿，并在体外抑制破骨细胞分化和破骨细胞生成标记物的 mRNA 水平。这些结果表明 A3373 具有治疗 RA 的潜力。