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 [Ca2+](i), a second messenger of cellular activation, in human monocytic Mono Mac 6 (MM6) cells. LPA and S1P induced [Ca2+](i) transients with EC50 values of 47 and 340 nM, respectively. Ca2+ signals evoked by LPA and S1P originated mainly from the stimulation of Ca2+ 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 Ca2+ signal. Notably, serum and minimally modified LDL (mm-LDL) evoked [Ca2+](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/Ca2+ 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. (C) 2002 Elsevier Science Inc. All rights reserved.