Group V secretory PLA2 regulates TLR2-dependent eicosanoid generation in mouse mast cells through amplification of ERK and cPLA2alpha activation.
Mast cells may be activated through Toll-like receptors (TLRs) for the dose- and time-dependent release of eicosanoids. However, the signaling mechanisms of TLR-dependent rapid eicosanoid generation are not known. We previously reported a role for group V secretory phospholipase A(2) (PLA(2)) in regulating phagocytosis of zymosan and the ensuing eicosanoid generation in mouse resident peritoneal macrophages, suggesting a role for the enzyme in innate immunity. In the present study, we have used gene knockout mice to define an essential role for MyD88 and cytosolic PLA(2)alpha in TLR2-dependent eicosanoid generation. Furthermore, in mast cells lacking group V secretory PLA(2), the time course of phosphorylation of ERK1/2 and of cPLA(2)alpha was markedly truncated, leading to attenuation of eicosanoid generation in response to stimulation through TLR2, but not through c-kit or FcepsilonRI. These findings provide the first dissection of the mechanisms of TLR-dependent rapid eicosanoid generation, which is MyD88-dependent, requires cPLA(2)alpha, and is amplified by group V sPLA(2) through its regulation of the sequential phosphorylation and activation of ERK1/2 and cPLA(2)alpha. The findings support the suggestion that group V sPLA(2) regulates innate immune responses.
Kikawada
Eriya
E
Department of Medicine, Harvard Medical School, Boston, MA, USA.
Bonventre
Joseph V
JV
Arm
Jonathan P
JP
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology; D018929:Cell Culture Techniques; D015777:Eicosanoids / Q000096:biosynthesis*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics*; D054505:Group V Phospholipases A2; D007113:Immunity, Innate; D007073:Immunoglobulin E / Q000494:pharmacology; D007700:Kinetics; D008407:Mast Cells / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010741:Phospholipases A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054467:Phospholipases A2; D010766:Phosphorylation; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
D015777:Eicosanoids; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D016718:Arachidonic Acid; D007073:Immunoglobulin E; D048049:Extracellular Signal-Regulated MAP Kinases; D010741:Phospholipases A; D054505:Group V Phospholipases A2; D054467:Phospholipases A2; C516300:Pla2g5 protein, mouse