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

Cristina Andrei, Paola Margiocco, Alessandro Poggi, Lavinia V. Lotti, M. R. Torrisi, Anna Rubartelli

Research output: Contribution to journalArticle

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 Ca 2+ 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.

Original languageEnglish
Pages (from-to)9745-9750
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number26
DOIs
Publication statusPublished - Jun 29 2004

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ASJC Scopus subject areas

  • Genetics
  • General

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