Phospholipases C and A2 control lysosome-mediated IL-1 beta secretion: Implications for inflammatory processes.
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.
Andrei
Cristina
C
Cell Transport Unit, Department of Oncogenesis, National Cancer Research Institute, 16132 Genoa, Italy.
Margiocco
Paola
P
Poggi
Alessandro
A
Lotti
Lavinia V
LV
Torrisi
M R
MR
Rubartelli
Anna
A
D000255:Adenosine Triphosphate / Q000494:pharmacology; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors; D002402:Cathepsin D / Q000378:metabolism; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005089:Exocytosis / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007375:Interleukin-1 / Q000378:metabolism*; D008247:Lysosomes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009636:Norbornanes; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D001952:Bridged-Ring Compounds; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007375:Interleukin-1; D009636:Norbornanes; D013859:Thiocarbamates; D013871:Thiones; C046498:tricyclodecane-9-yl-xanthogenate; D000255:Adenosine Triphosphate; D010741:Phospholipases A; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C; D020170:Caspase 1; D002402:Cathepsin D; D011188:Potassium; D002118:Calcium