Activation of human monocytic cells by lysophosphatidic acid and sphingosine-1-phosphate.
Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are serum-borne lipid mediators with potential proinflammatory and atherogenic properties. We studied the effects of LPA and S1P on [Ca(2+)](i), a second messenger of cellular activation, in human monocytic Mono Mac 6 (MM6) cells. LPA and S1P induced [Ca(2+)](i) transients with EC(50) values of 47 and 340 nM, respectively. Ca(2+) signals evoked by LPA and S1P originated mainly from the stimulation of Ca(2+) entry, were blocked by the phospholipase C inhibitor U73122, and were inhibited by pertussis toxin. The LPA(1) and LPA(3) receptor antagonist dioctylglycerol pyrophosphate inhibited the LPA-induced Ca(2+) signal. Notably, serum and minimally modified LDL (mm-LDL) evoked [Ca(2+)](i) increases that were mediated entirely through activation of LPA receptors. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis showed the presence of the LPA and S1P receptor subtypes LPA(1), LPA(2,) S1P(1), S1P(2), S1P(4) in MM6 cells, human monocytes and macrophages. Together these results indicate that LPA, mm-LDL and serum induce via activation of the LPA(1) receptor a G(i)/phospholipase C/Ca(2+) signalling pathway in monocytes. Our study is the first report showing the receptor-mediated activation of human monocytic cells by low nanomolar concentrations of LPA and S1P, and suggests a role of these lipid mediators in inflammation and atherogenesis.
Fueller
Markus
M
Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Klinikum der Universität München, Pettenkoferstr 9, D 80336 Munich, Germany.
Wang
De An
DA
Tigyi
Gabor
G
Siess
Wolfgang
W
D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D004963:Estrenes / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D011760:Pyrrolidinones / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000032:analysis / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid; D049312:Receptors, Lysophospholipid; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
D004963:Estrenes; D008077:Lipoproteins, LDL; D008246:Lysophospholipids; D011760:Pyrrolidinones; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D049312:Receptors, Lysophospholipid; C099252:oxidized low density lipoprotein; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C060506:sphingosine 1-phosphate; D010738:Type C Phospholipases; D013110:Sphingosine; D002118:Calcium