Robertson Stacy, Martínez Gonzalo J, Payet Cloe A, Barraclough Jennifer Y, Celermajer David S, Bursill Christina, Patel Sanjay
Heart Research Institute, Sydney, New South Wales 2042, Australia Sydney Medical School, The University of Sydney, New South Wales 2006, Australia
Sydney Medical School, The University of Sydney, New South Wales 2006, Australia Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales 2050, Australia División de Enfermedades Cardiovasculares, Pontificia Universidad Católica de Chile, Santiago, Chile.
Clin Sci (Lond). 2016 Jul 1;130(14):1237-46. doi: 10.1042/CS20160090. Epub 2016 Apr 21.
Inflammasome activation, with subsequent release of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, has recently been implicated in atherosclerosis-associated inflammation. This study aims to assess in acute coronary syndrome (ACS) patients (1) inflammasome activation in circulating monocytes and (2) whether short-term oral colchicine, a recognized anti-inflammatory agent that has been shown to be cardio-protective in clinical studies, might acutely suppress inflammasome-dependent inflammation. ACS patients (n=21) were randomized to oral colchicine (1 mg followed by 0.5 mg 1 h later) or no treatment, and compared with untreated healthy controls (n=9). Peripheral venous blood was sampled pre- (day 1) and 24 h post- (day 2) treatment. Monocytes were cultured and stimulated with ATP. Analysis of key inflammasome markers was performed by ELISA. IL-1β secretion increased by 580.4% (P<0.01) in ACS patients compared with controls but only with ATP stimulation. Untreated ACS patients secreted significantly higher levels of IL-18 compared with healthy controls independent of ATP stimulation (P<0.05). Colchicine treatment in ACS patients markedly reduced intracellular and secreted levels of IL-1β compared with pre-treatment levels (P<0.05 for both), as well as significantly reducing pro-caspase-1 mRNA levels by 57.7% and secreted caspase-1 protein levels by 30.2% compared with untreated patients (P<0.05 for both). Monocytes from ACS patients are 'primed' to secrete inflammasome-related cytokines and short-term colchicine acutely and markedly suppresses monocyte caspase-1 activity, thereby reducing monocyte secretion of IL-1β.
炎性小体激活以及随后促炎细胞因子白细胞介素 -1β（IL-1β）和IL-18的释放，最近被认为与动脉粥样硬化相关的炎症有关。本研究旨在评估急性冠状动脉综合征（ACS）患者：（1）循环单核细胞中的炎性小体激活情况；（2）短期口服秋水仙碱（一种在临床研究中已显示具有心脏保护作用的公认抗炎药）是否能急性抑制炎性小体依赖性炎症。将ACS患者（n = 21）随机分为口服秋水仙碱组（1 mg，1小时后再服0.5 mg）或不治疗组，并与未治疗的健康对照组（n = 9）进行比较。在治疗前（第1天）和治疗后24小时（第2天）采集外周静脉血。培养单核细胞并用ATP刺激。通过酶联免疫吸附测定法（ELISA）分析关键炎性小体标志物。与对照组相比，ACS患者中IL-1β分泌增加了580.4%（P<0.01），但仅在ATP刺激时出现这种情况。未治疗的ACS患者与健康对照组相比，无论是否有ATP刺激，IL-18分泌水平均显著更高（P<0.05）。与治疗前水平相比，ACS患者接受秋水仙碱治疗后，细胞内和分泌的IL-1β水平均显著降低（两者P<0.05），与未治疗患者相比，促半胱天冬酶 -1 mRNA水平显著降低57.7%，分泌的半胱天冬酶 -1蛋白水平降低30.2%（两者P<0.05）。ACS患者的单核细胞“预激活”以分泌炎性小体相关细胞因子，短期秋水仙碱可急性且显著抑制单核细胞半胱天冬酶 -1活性，从而减少单核细胞IL-1β的分泌。
