Secretory phospholipase A2 generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells.
Nonpancreatic secretory phospholipase A2 (sPLA2) displays proinflammatory properties; however, its physiological substrate is not identified. Although inactive toward intact cells, sPLA2 hydrolyzed phospholipids in membrane microvesicles shed from Ca(2+)-loaded erythrocytes as well as from platelets and from whole blood cells challenged with inflammatory stimuli. sPLA2 was stimulated upon degradation of sphingomyelin (SPH) and produced lysophosphatidic acid (LPA), which induced platelet aggregation. Finally, lysophospholipid-containing vesicles and sPLA2 were detected in inflammatory fluids in relative proportions identical to those used in vitro. We conclude that upon loss of phospholipid asymmetry, cell-derived microvesicles provide a preferential substrate for sPLA2. SPH hydrolysis, which is provoked by various cytokines, regulates sPLA2 activity, and the novel lipid mediator LPA can be generated by this pathway.
Fourcade
O
O
Institut National de la Santé et de la Recherche Médicale, Unité 326, Phospholipides Membranaires, Signalisation Cellulaire et Lipoprotéines, Hôpital Purpan, Toulouse, France.
Simon
M F
MF
Viodé
C
C
Rugani
N
N
Leballe
F
F
Ragab
A
A
Fournié
B
B
Sarda
L
L
Chap
H
H
D000818:Animals; D001483:Base Sequence; D002462:Cell Membrane / Q000201:enzymology; D017931:DNA Primers; D004910:Erythrocyte Membrane / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008246:Lysophospholipids / Q000378:metabolism* / Q000494:pharmacology; D008563:Membrane Lipids / Q000378:metabolism*; D008969:Molecular Sequence Data; D010712:Phosphatidic Acids / Q000378:metabolism; D010741:Phospholipases A / Q000096:biosynthesis / Q000378:metabolism*; D054467:Phospholipases A2; D010974:Platelet Aggregation / Q000187:drug effects; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D013552:Swine
D017931:DNA Primers; D008246:Lysophospholipids; D008563:Membrane Lipids; D010712:Phosphatidic Acids; D011994:Recombinant Proteins; D010741:Phospholipases A; D054467:Phospholipases A2