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Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9745-50. Epub 2004 Jun 10.

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

Author information

  • 1Cell Transport Unit, Department of Oncogenesis, National Cancer Research Institute, 16132 Genoa, Italy.

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 Ca(2+) influx and activation of three phospholipases: phosphatidylcholine-specific phospholipase C and calcium-independent and -dependent phospholipase A(2). Whereas calcium-independent phospholipase A(2) is involved in processing, phosphatidylcholine-specific phospholipase C and calcium-dependent phospholipase A(2) 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 A(2). This activation is ultimately responsible for lysosome exocytosis and IL-1 beta secretion.

Comment in

  • IL-1beta: an endosomal exit. [Proc Natl Acad Sci U S A. 2004]
PMID:
15192144
[PubMed - indexed for MEDLINE]
PMCID:
PMC470745
Free PMC Article

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