Lu Miaomiao, Yang Wenjun, Peng Zhangzhe, Zhang Jin, Mei Wenjuan, Liu Chunyan, Tang Juan, Ma Hong, Yuan Xiangning, Meng Jie, Lv Ben, Liu Jishi, Hu Gaoyun, Tao Lijian
Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Nephrology, The First Affiliated of Liaoning Medical University, Jinzhou, Liaoning 121001, China.
Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Int Immunopharmacol. 2015 Jul;27(1):148-53. doi: 10.1016/j.intimp.2015.05.008. Epub 2015 May 14.
Interleukin-1 beta (IL-1β) is a potent pro-inflammatory and pro-fibrotic cytokine that plays an important role in renal fibrosis. Fluorofenidone (AKF-PD) is a novel pyridone agent that exerts a strong renal anti-fibrotic effect. We previously found that administration of AKF-PD could significantly attenuate IL-1β production in vitro and in vivo. However, the underlying mechanism is not fully understood. Here we show that AKF-PD has no effect on the expression of pro-IL-1β in activated mouse macrophages in vitro. Instead, AKF-PD inhibits the inflammasome, lowering caspase-1 levels and thereby decreasing cleavage of pro-IL-1β into IL-1β. AKF-PD was found to block inflammasome activity induced by various signals, including ATP, alum crystals, and Salmonella typhimurium. These results provide a novel mechanistic insight into how AKF-PD exerts its anti-inflammatory and anti-fibrotic activities, and suggest that AKF-PD might block IL-1β production via suppression of inflammasomes in renal fibrosis. In addition, the results suggest that AKF-PD may be of therapeutic potential in other inflammasome-related diseases.
白细胞介素-1β（IL-1β）是一种强效的促炎和促纤维化细胞因子，在肾纤维化中起重要作用。氟非尼酮（AKF-PD）是一种新型吡啶酮类药物，具有强大的肾脏抗纤维化作用。我们之前发现，给予AKF-PD可在体外和体内显著减弱IL-1β的产生。然而，其潜在机制尚未完全阐明。在此我们表明，AKF-PD在体外对活化的小鼠巨噬细胞中前体IL-1β的表达没有影响。相反，AKF-PD抑制炎性小体，降低半胱天冬酶-1水平，从而减少前体IL-1β裂解为IL-1β。发现AKF-PD可阻断由各种信号诱导的炎性小体活性，包括三磷酸腺苷（ATP）、明矾晶体和鼠伤寒沙门氏菌。这些结果为AKF-PD如何发挥其抗炎和抗纤维化活性提供了新的机制性见解，并表明AKF-PD可能通过抑制肾纤维化中的炎性小体来阻断IL-1β的产生。此外，结果表明AKF-PD在其他与炎性小体相关的疾病中可能具有治疗潜力。
