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J Biol Chem. 2014 Jun 6;289(23):16214-22. doi: 10.1074/jbc.M114.571505. Epub 2014 Apr 30.

3-Hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin)-induced 28-kDa interleukin-1β interferes with mature IL-1β signaling.

Author information

1
From the Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and.
2
NIAID, National Institutes of Health, Rockville, Maryland 20852.
3
From the Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and donghai.wang@umassmed.edu.

Abstract

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.

KEYWORDS:

Atherosclerosis; Caspase; Immunology; Inflammation; Innate Immunity; Interleukin

PMID:
24790079
PMCID:
PMC4047391
DOI:
10.1074/jbc.M114.571505
[Indexed for MEDLINE]
Free PMC Article

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