![]() Pro-IL-1 β is rapidly induced upon exposure of inflammatory cells to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) that bind to pattern recognition receptors (PRRs) to upregulate proinflammatory gene expression. 1 IL-1 β is produced as an inactive precursor called pro-IL-1 β mainly by inflammatory cells of myeloid lineage. Interleukin-1 β (IL-1 β) is a proinflammatory cytokine that is central for host responses to infection. These discoveries reveal key processes at the initiation of an inflammatory response and deliver new insights into the mechanisms of protein release. The mechanism of membrane permeabilisation leading to IL-1 β release is distinct from the unconventional secretory mechanism employed by its structural homologues fibroblast growth factor 2 (FGF2) or IL-1 α, a process that involves the formation of membrane pores but does not result in cell death. Thus, in macrophages the release of IL-1 β in response to inflammasome activation appears to be a secretory process independent of nonspecific leakage of proteins during cell death. Using a novel and reversible pharmacological inhibitor of the IL-1 β release process, in combination with biochemical, biophysical, and real-time single-cell confocal microscopy with macrophage cells expressing Venus-labelled IL-1 β, we have discovered that the secretion of IL-1 β after inflammasome activation requires membrane permeabilisation, and occurs in parallel with the death of the secreting cell. Crucially, its secretion depends upon the processing of a precursor form following the activation of the multimolecular inflammasome complex. IL-1 β is not secreted through the conventional ER–Golgi route of protein secretion, and to date its mechanism of release has been unknown. Interleukin-1 β (IL-1 β) is a critical regulator of the inflammatory response.
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