Department of Herbology, School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea.
Department of Herbology, School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 540-749, South Korea; Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan, Jeonbuk 54538, South Korea.
Int Immunopharmacol. 2019 Apr;69:169-177. doi: 10.1016/j.intimp.2019.01.043. Epub 2019 Feb 1.
Inflammasomes promote the production of pro-inflammatory cytokines, such as interleukin (IL)-1β and IL-18, which are the representative mediators of inflammation. Abnormal activation of inflammasomes leads to the development of inflammatory diseases such as acute pancreatitis (AP). In this study, we demonstrate the inhibitory effects of a new natural compound fraxinellone on inflammasome formation and examine the role of inflammasomes in a mouse model of AP. AP was induced with hourly intraperitoneal injections of supramaximal concentrations of the stable cholecystokinin analogue cerulein (50 μg/kg) for 6 h. Mice were sacrificed 6 h after the final cerulein injection. Blood and pancreas samples were obtained for further experiments. Intraperitoneal injection of fraxinellone significantly inhibited the pancreatic activation of multiple inflammasome molecules such as NACHT, LRR and PYD domains-containing protein 3 (NLRP3), PY-CARD, caspase-1, IL-18, and IL-1β during AP. In addition, fraxinellone treatment inhibited pancreatic injury, elevation in serum amylase and lipase activities, and infiltration of inflammatory cells such as neutrophils and macrophages but had no effect on pancreatic edema. To investigate whether inflammasome activation leads to the infiltration of inflammatory cells, we used parthenolide, a well-known natural inhibitor, and IL-1 receptor antagonist mice. The inhibition of inflammasome activation by pharmacological/or genetic modification restricted the infiltration of inflammatory cells, but not edema, consistent with the results observed with fraxinellone. Taken together, our study highlights fraxinellone as a natural inhibitor of inflammasomes and that inflammasome inhibition may lead to the suppression of inflammatory cells during AP.
炎症小体促进促炎细胞因子（如白细胞介素（IL）-1β和 IL-18）的产生，这些细胞因子是炎症的代表性介质。炎症小体的异常激活导致急性胰腺炎（AP）等炎症性疾病的发生。在这项研究中，我们证明了一种新的天然化合物 fraxinellone 对炎症小体形成的抑制作用，并研究了炎症小体在 AP 小鼠模型中的作用。通过每小时腹腔内注射最大稳定胆囊收缩素类似物 cerulein（50μg/kg）6 小时来诱导 AP。在最后一次 cerulein 注射后 6 小时处死小鼠。采集血液和胰腺样本进行进一步实验。腹腔内注射 fraxinellone 显著抑制了 AP 期间多种炎症小体分子（如 NACHT、LRR 和 PYD 结构域包含蛋白 3（NLRP3）、PY-CARD、半胱天冬酶-1、IL-18 和 IL-1β）的胰腺激活。此外，fraxinellone 治疗抑制了胰腺损伤、血清淀粉酶和脂肪酶活性的升高以及中性粒细胞和巨噬细胞等炎症细胞的浸润，但对胰腺水肿没有影响。为了研究炎症小体激活是否导致炎症细胞浸润，我们使用了 parthenolide，一种众所周知的天然抑制剂，和 IL-1 受体拮抗剂小鼠。通过药理学/遗传修饰抑制炎症小体激活限制了炎症细胞的浸润，但不影响水肿，与 fraxinellone 观察到的结果一致。综上所述，我们的研究强调了 fraxinellone 作为炎症小体的天然抑制剂，并且炎症小体抑制可能导致 AP 期间炎症细胞的抑制。
