From the Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and.
NIAID, National Institutes of Health, Rockville, Maryland 20852.
J Biol Chem. 2014 Jun 6;289(23):16214-22. doi: 10.1074/jbc.M114.571505. Epub 2014 Apr 30.
Multiple clinical trials have shown that the 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors known as statins have anti-inflammatory effects. However, the underlying molecular mechanism remains unclear. The proinflammatory cytokine interleukin-1β (IL-1β) is synthesized as a non-active precursor. The 31-kDa pro-IL-1β is processed into the 17-kDa active form by caspase-1-activating inflammasomes. Here, we report a novel signaling pathway induced by statins, which leads to processing of pro-IL-1β into an intermediate 28-kDa form. This statin-induced IL-1β processing is independent of caspase-1- activating inflammasomes. The 28-kDa form of IL-1β cannot activate interleukin-1 receptor-1 (IL1R1) to signal inflammatory responses. Instead, it interferes with mature IL-1β signaling through IL-1R1 and therefore may dampen inflammatory responses initiated by mature IL-1β. These results may provide new clues to explain the anti-inflammatory effects of statins.
多项临床试验表明，被称为他汀类药物的 3-羟基-3-甲基戊二酰辅酶 A（HMG-CoA）还原酶抑制剂具有抗炎作用。然而，其潜在的分子机制尚不清楚。促炎细胞因子白细胞介素-1β（IL-1β）以前体的非活性形式合成。31kDa 的前体 pro-IL-1β 通过 caspase-1 激活的炎性小体被加工成 17kDa 的活性形式。在这里，我们报告了他汀类药物诱导的一种新的信号通路，该通路导致前体 IL-1β加工成中间 28kDa 形式。这种他汀类药物诱导的 IL-1β 加工不依赖于 caspase-1 激活的炎性小体。28kDa 的 IL-1β 形式不能激活白细胞介素-1 受体-1（IL1R1）以发出炎症反应信号。相反，它通过 IL1R1 干扰成熟的 IL-1β 信号转导，因此可能会抑制由成熟的 IL-1β 引发的炎症反应。这些结果可能为解释他汀类药物的抗炎作用提供新的线索。
