Fluorofenidone inhibits macrophage IL-1β production by suppressing inflammasome activity
Fluorofenidone inhibits macrophage IL-1β production by suppressing inflammasome activity
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DOI：
10.1016/j.intimp.2015.05.008
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发表时间：
2015-07-01
影响因子：
5.6
通讯作者：
Tao, Lijian
中科院分区：
文献类型：
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作者：
Lu, Miaomiao;Yang, Wenjun;Tao, Lijian
白细胞介素-1 β (IL-1 β)是一种有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）是一种新型吡酮类药物，具有较强的抗肾纤维化作用。我们之前发现AKF-PD可以显著降低体内和体外IL-1 β的产生。然而，其潜在的机制尚不完全清楚。本研究表明，AKF-PD对体外活化小鼠巨噬细胞中pro-IL-1 β的表达没有影响。相反，AKF-PD抑制炎性小体，降低caspase-1水平，从而减少原IL-1 β裂解为IL-1 β。研究发现，AKF-PD可阻断ATP、明矾晶体和鼠伤寒沙门氏菌等多种信号诱导的炎性体活性。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见解，并表明AKF-PD可能通过抑制肾纤维化中的炎症小体来阻断IL-1 β的产生。此外，结果表明AKF-PD可能在其他炎性小体相关疾病中具有治疗潜力。(C) 2015 Elsevier B.V.版权所有
Interleukin-1 beta (IL-1 beta) 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-1 beta 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-1 beta in activated mouse macrophages in vitro. Instead, AKF-PD inhibits the inflammasome, lowering caspase-1 levels and thereby decreasing cleavage of pro-IL-1 beta into IL-1 beta. 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-1 beta 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. (C) 2015 Elsevier B.V. All rights reserved.