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PNAS 101 (26): 9745-9750

Copyright © 2004 by the National Academy of Sciences.

From The Cover

Immunology

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

Cristina Andrei *, Paola Margiocco *, Alessandro Poggi {dagger}, Lavinia V. Lotti {ddagger}, M. R. Torrisi {ddagger}, and Anna Rubartelli *, §

*Cell Transport Unit and {dagger}Laboratory of Immunology, Department of Oncogenesis, National Cancer Research Institute, 16132 Genoa, Italy; and {ddagger}Department of Experimental Medicine and Pathology, University of Rome La Sapienza, 00161 Rome, Italy

Edited by Charles A. Dinarello, University of Colorado Health Sciences Center, Denver, CO, and approved May 12, 2004

Received for publication December 23, 2003.

Abstract: Blocking the activity of IL-1{beta} 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-1{beta} release. These are still unclear as IL-1{beta}, lacking a secretory signal peptide, follows a nonclassical pathway of secretion. Here, we analyze the molecular mechanism(s) undergoing IL-1{beta} 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-1{beta} are targeted in part to specialized secretory lysosomes, where they colocalize with other lysosomal proteins. Externalization of mature IL-1{beta} 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-1{beta} secretion.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: [Ca2+]i, intracellular free calcium concentration; PLC, phospholipase C; PC-PLC, phosphatidylcholine-specific PLC; PLD, phospholipase D; iPLA2, calcium-independent phospholipase A2; cPLA2, calcium-dependent phospholipase A2; LPS, lipopolysaccharide; AACOCF3, arachidonyl trifluoromethylketone; ac-YVAD-cmk, acetyl-Tyr-Val-Ala-Aspchloromethyl ketone; LDH, lactate dehydrogenase.

§ To whom correspondence should be addressed. E-mail: anna.rubartelli{at}istge.it.

© 2004 by The National Academy of Sciences of the USA

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