The pro-inflammatory cytokine interleukin-1β (IL-1β) is implicated in acute and chronic inflammatory diseases. However, despite its biological importance, the mechanisms involved in its processing and trafficking are poorly defined. On , David Brough and Nancy Rothwell define the cellular mechanisms involved in IL-1β post-translational processing and provide insight into the atypical pathway by which IL-1β is generated. The authors demonstrate that cleavage of the precursor polypeptide Pro-IL-1β by caspase-1 occurs predominantly in the cytosol following activation of the proinflammatory purinergic receptor P2X7 by ATP and suggest a lack of lysosomal involvement. Structural changes to the cell, following caspase-1 activation, promote the cellular release of IL-1β, which itself precedes cell death. The authors propose that IL-1β processing occurs in the cytosol by a mechanism that resembles the programmed cell death process, pyroptosis, which requires caspase-1. Understanding mechanisms of bioactive IL-1β generation may help identify new targets for anti-IL-1β therapies and improve our understanding of inflammatory processes during disease.
