Phospholipases C and A₂ control lysosome-mediated IL-1β secretion: Implications for inflammatory processes

Abstract

Blocking the activity of IL-1β has entered the clinical arena of treating autoimmune diseases. However, a successful outcome of this approach requires a clear definition of the mechanisms controlling IL-1β release. These are still unclear as IL-1β, lacking a secretory signal peptide, follows a nonclassical pathway of secretion. Here, we analyze the molecular mechanism(s) undergoing IL-1β processing and release in human monocytes and provide a unifying model for the regulated secretion of the cytokine. Our data show that in a first step, pro-caspase-1 and endotoxin-induced pro-IL-1β are targeted in part to specialized secretory lysosomes, where they colocalize with other lysosomal proteins. Externalization of mature IL-1β and caspase-1 together with lysosomal proteins is then facilitated by extracellular ATP. ATP triggers the efflux of K⁺ from the cell, followed by Ca²⁺ influx and activation of three phospholipases: phosphatidylcholine-specific phospholipase C and calcium-independent and -dependent phospholipase A₂. Whereas calcium-independent phospholipase A₂ is involved in processing, phosphatidylcholine-specific phospholipase C and calcium-dependent phospholipase A₂ are required for secretion. Dissection of the events that follow ATP triggering allowed to demonstrate that K⁺ efflux is responsible for phosphatidylcholine-specific phospholipase C induction, which in turn allows the rise in intracellular free calcium concentration required for activation of phospholipase A₂. This activation is ultimately responsible for lysosome exocytosis and IL-1β secretion.