Fcgamma RI-triggered generation of arachidonic acid and eicosanoids requires iPLA2 but not cPLA2 in human monocytic cells.
Aggregation of receptors for immunoglobulin G (FcgammaRs) on myeloid cells activates a series of events that are key in the inflammatory response and that can ultimately lead to targeted cell killing by antibody-directed cellular cytotoxicity. Generation of lipid-derived proinflammatory mediators is an important component of the integrated cellular response mediated by receptors for the constant region of immunoglobulins (Fc). We have demonstrated previously that, in interferon-gamma-primed U937 cells, the high affinity receptor for IgG, FcgammaRI, is coupled to a novel intracellular signaling pathway that involves the sequential activation of phospholipase D, sphingosine kinase, calcium transients, and protein kinase C isoforms, leading to the activation of the NADPH-oxidative burst. Here, we investigate the nature of the phospholipase that regulates arachidonic acid and eicosanoid production. Our data show that FcgammaRI couples to iPLA(2)beta for the release of arachidonic acid and the generation of leukotriene B(4) and prostaglandin E(2). Activation of iPLA(2)beta was protein kinase C-dependent; on the other hand, platelet-activating factor triggered cPLA(2)alpha by means of the mitogen-activated protein kinase pathway. These studies demonstrate that intracellular PLA(2)s can be selectively regulated by different stimuli and suggest a critical role for iPLA(2)beta in the intracellular signaling cascades initiated by FcgammaRI and its functional role in the generation of key inflammatory mediators.
Tay
Hwee Kee
HK
Department of Physiology, Faculty of Medicine, National University of Singapore, Singapore 117597.
Melendez
Alirio J
AJ
D016718:Arachidonic Acid / Q000737:chemistry / Q000378:metabolism*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D054522:Group VI Phospholipases A2; D006801:Humans; D007249:Inflammation; D007975:Leukotriene B4 / Q000737:chemistry / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D020935:MAP Kinase Signaling System; D008856:Microscopy, Fluorescence; D009000:Monocytes / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010739:Phospholipase D / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000737:chemistry / Q000378:metabolism; D021381:Protein Transport; D017452:Receptors, IgG / Q000378:metabolism*; D016897:Respiratory Burst; D015398:Signal Transduction; D013997:Time Factors; D020298:U937 Cells
D015777:Eicosanoids; C485701:Fcgr1 protein, mouse; D008055:Lipids; D020033:Protein Isoforms; D017452:Receptors, IgG; D007975:Leukotriene B4; D016718:Arachidonic Acid; D009249:NADP; D011493:Protein Kinase C; D010741:Phospholipases A; D054522:Group VI Phospholipases A2; C516475:PLA2G6 protein, human; C516476:Pla2g6 protein, mouse; D010739:Phospholipase D; D015232:Dinoprostone; D002118:Calcium