HMG-CoA reductase inhibitors (statins)-induced 28-kDa interleukin-1{beta} interferes with mature IL-1{beta} signaling [Metabolism]

April 30th, 2014 by Davaro, F., Forde, S. D., Garfield, M., Jiang, Z., Halmen, K., Tamburro, N. D., Kurt-Jones, E. A., Fitzgerald, K. A., Golenbock, D. T., Wang, D.

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 IL-1RI to signal inflammatory responses. Instead, it interferes with mature IL-1β signaling through IL-1R 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.