3-Hydroxyl-3-methylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitor (Statin)-induced 28-kDa Interleukin-1β Interferes with Mature IL-1β Signaling

被引：27

作者：

Davaro, Facundo ^{[1
]}

Forde, Sorcha D. ^{[1
]}

Garfield, Mark ^{[2
]}

Jiang, Zhaozhao ^{[1
]}

Halmen, Kristen ^{[1
]}

Tamburro, Nelsy Depaula ^{[1
]}

Kurt-Jones, Evelyn ^{[1
]}

Fitzgerald, Katherine A. ^{[1
]}

Golenbock, Douglas T. ^{[1
]}

Wang, Donghai ^{[1
]}

机构：

[1] Univ Massachusetts, Sch Med, Dept Med, Div Infect Dis & Immunol, Worcester, MA 01605 USA

[2] NIAID, NIH, Rockville, MD 20852 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2014年 / 289卷 / 23期

基金：

美国国家卫生研究院;

关键词：

CORONARY EVENTS; IN-VITRO; ATORVASTATIN; RELEASE; STATINS; INFLAMMASOMES; INFLAMMATION; SIMVASTATIN; CASPASE-1; CELLS;

D O I：

10.1074/jbc.M114.571505

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-1 beta (IL-1 beta) is synthesized as a non-active precursor. The 31-kDa pro-IL-1 beta 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-1 beta into an intermediate 28-kDa form. This statin-induced IL-1 beta processing is independent of caspase-1-activating inflammasomes. The 28-kDa form of IL-1 beta cannot activate interleukin-1 receptor-1 (IL1R1) to signal inflammatory responses. Instead, it interferes with mature IL-1 beta signaling through IL-1R1 and therefore may dampen inflammatory responses initiated by mature IL-1 beta. These results may provide new clues to explain the anti-inflammatory effects of statins.

引用

页码：16214 / 16222

页数：9

共 45 条

[1] Effect of atorvastatin with or without prednisolone on Freund's adjuvant induced-arthritis in rats [J].