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

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.