HMG-CoA reductase inhibition induces IL-1β release through Rac1/PI3K/PKB-dependent caspase-1 activation
HMG-CoA reductase inhibition induces IL-1β release through Rac1/PI3K/PKB-dependent caspase-1 activation
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DOI：
10.1182/blood-2008-03-144667
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发表时间：
2008-11-01
期刊：
影响因子：
20.3
通讯作者：
Coffer, Paul J.
中科院分区：
文献类型：
--
作者：
Kuijk, Loes M.;Beekman, Jeffrey M.;Coffer, Paul J.
甲羟戊酸激酶缺乏症（MKD）是一种自身炎症性疾病，其特征是反复发热发作，由类异戊二烯生物合成紊乱引起。MKD患者的脂多糖刺激的外周血单核细胞分泌高水平的白细胞介素-1 β（IL-1 β），因为存在过度活跃的半胱天冬酶-1，这被认为是炎症复发的主要原因。在这里，我们表明，通过辛伐他汀治疗，模拟MKD，抑制HMG-CoA还原酶，导致Rac 1/PI 3 K依赖性方式的IL-1 β分泌增加。辛伐他汀处理被发现激活蛋白激酶B（PKB）/c-akt，PI 3 K的主要效应物，并且组成性活性PKB的异位表达足以诱导IL-1 β释放。小的GTdR Rac 1被辛伐他汀激活，这是PKB激活和IL-1 β分泌所必需的。IL-1 β的释放是由caspase-1介导的，辛伐他汀处理导致caspase-1活性以Rac 1/PI 3 K依赖性方式增加。这些数据表明，在MKD中，失调的类异戊二烯生物合成激活Rac 1/PI 3 K/PKB，导致半胱天冬酶-1激活和IL-1 β释放增加。重要的是，抑制从MKD患者分离的外周血单核细胞中的Rac 1导致IL-1 β释放的显著减少。这些数据表明，Rac 1的药理学抑制可以为MKD的治疗提供一种新的治疗策略。（血。2008; 112：3563-3573）
Mevalonate kinase deficiency (MKD) is an autoinflammatory disorder characterized by recurring fever episodes and results from disturbed isoprenoid biosynthesis. Lipopolysaccharide-stimulated peripheral blood mononuclear cells from MKD patients secrete high levels of interleukin-1 beta (IL-1 beta) because of the presence of hyperactive caspase-1, and this has been proposed to be the primary cause of recurring inflammation. Here we show that inhibition of HMG-CoA reductase by simvastatin treatment, mimicking MKD, results in increased IL-1 beta secretion in a Rac1/PI3K-dependent manner. Simvastatin treatment was found to activate protein kinase B (PKB)/c-akt, a primary effector of PI3K, and ectopic expression of constitutively active PKB was sufficient to induce IL-1 beta release. The small GTPase Rac1 was activated by simvastatin, and this was required for both PKB activation and IL-1 beta secretion. IL-1 beta release is mediated by caspase-1, and simvastatin treatment resulted in increased caspase-1 activity in a Rac1/PI3K-dependent manner. These data suggest that, in MKD, dysregulated isoprenoid biosynthesis activates Rac1/PI3K/PKB, resulting in caspase-1 activation with increased IL-1 beta release. Importantly, inhibition of Rac1 in peripheral blood mononuclear cells isolated from MKD patients resulted in a dramatic reduction in IL-1 beta release. These data suggest that pharmacologic inhibition of Rac1 could provide a novel therapeutic strategy for treatment of MKD. (Blood. 2008; 112: 3563-3573)