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

Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9745-50. doi: 10.1073/pnas.0308558101. Epub 2004 Jun 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / pharmacology
  • Bridged-Ring Compounds / pharmacology
  • Calcium / metabolism
  • Caspase 1 / metabolism
  • Caspase Inhibitors
  • Cathepsin D / metabolism
  • Cells, Cultured
  • Cysteine Proteinase Inhibitors / pharmacology
  • Enzyme Activation / drug effects
  • Exocytosis / drug effects
  • Humans
  • Inflammation / metabolism
  • Inflammation / pathology
  • Interleukin-1 / metabolism*
  • Lysosomes / chemistry
  • Lysosomes / drug effects
  • Lysosomes / metabolism*
  • Models, Biological
  • Monocytes / cytology
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Norbornanes
  • Phospholipases A / antagonists & inhibitors
  • Phospholipases A / metabolism*
  • Potassium / metabolism
  • Protein Processing, Post-Translational
  • Thiocarbamates
  • Thiones / pharmacology
  • Type C Phospholipases / antagonists & inhibitors
  • Type C Phospholipases / metabolism*


  • Bridged-Ring Compounds
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • Interleukin-1
  • Norbornanes
  • Thiocarbamates
  • Thiones
  • tricyclodecane-9-yl-xanthogenate
  • Adenosine Triphosphate
  • Phospholipases A
  • Type C Phospholipases
  • phosphatidylcholine-specific phospholipase C
  • Caspase 1
  • Cathepsin D
  • Potassium
  • Calcium