Title

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

UMMS Affiliation

Department of Medicine, Division of Infectious Diseases and Immunology

Date

6-6-2014

Document Type

Article

Subjects

Animals; Cells, Cultured; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Interleukin-1beta; Macrophages; Mice; Mice, Inbred C57BL; Signal Transduction

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

Rights and Permissions

Citation: J Biol Chem. 2014 Jun 6;289(23):16214-22. doi: 10.1074/jbc.M114.571505. Epub 2014 Apr 30. Link to article on publisher's site

Related Resources

Link to Article in PubMed

PubMed ID

24790079