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

Content Provider	PubMed Central
Author	Andrei, Cristina Paola, Margiocco Poggi, Alessandro Lotti, Lavinia V. Torrisi, M. R. Anna, Rubartelli
Copyright Year	2004
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.
Related Links	http://dx.doi.org/10.1073/pnas.0308558101
Ending Page	9750
Page Count	6
Starting Page	9745
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	26
Volume Number	101
Language	English
Publisher	National Academy of Sciences
Publisher Date	2004-06-29
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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