3-Hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin)-induced 28-kDa interleukin-1beta interferes with mature IL-1beta signaling
Department of Medicine, Division of Infectious Diseases and Immunology
Animals; Cells, 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
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.
DOI of Published Version
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
The Journal of biological chemistry
Davaro, Facundo; Forde, Sorcha D.; Garfield, Mark; Jiang, Zhaozhao; Halmen, Kristen A.; Tamburro, Nelsy DePaula; Kurt-Jones, Evelyn A.; Fitzgerald, Katherine A.; Golenbock, Douglas T.; and Wang, Donghai, "3-Hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin)-induced 28-kDa interleukin-1beta interferes with mature IL-1beta signaling" (2014). Infectious Diseases and Immunology Publications and Presentations. 174.