3-Hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin)-induced 28-kDa interleukin-1beta interferes with mature IL-1beta signaling
Authors
Davaro, FacundoForde, Sorcha D.
Garfield, Mark
Jiang, Zhaozhao
Halmen, Kristen A.
Tamburro, Nelsy DePaula
Kurt-Jones, Evelyn A.
Fitzgerald, Katherine A.
Golenbock, Douglas T.
Wang, Donghai
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDocument Type
Journal ArticlePublication Date
2014-06-06Keywords
AnimalsCells, Cultured
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Interleukin-1beta
Macrophages
Mice
Mice, Inbred C57BL
Signal Transduction
Biochemistry
Immunity
Immunology and Infectious Disease
Immunology of Infectious Disease
Medicinal-Pharmaceutical Chemistry
Metadata
Show full item recordAbstract
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.Source
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 siteDOI
10.1074/jbc.M114.571505Permanent Link to this Item
http://hdl.handle.net/20.500.14038/34952PubMed ID
24790079Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1074/jbc.M114.571505