Lysophosphatidylcholine transduces Ca2+ signaling via the platelet-activating factor receptor in macrophages

Abstract

To clarify the molecular mechanism underlying the lysophosphatidylcholine (LPC) signaling, we studied the effect of LPC on the intracellular free calcium concentration ([Ca2+]i) in murine peritoneal macrophages. LPC when added alone induced biphasic elevation of [Ca2+]i, which consisted of a rapid increase followed by sustained elevation. LPC, when added with equimolar cholesterol, induced only the rapid increase in [Ca2+]i, which was blocked by WEB-2086, a selective platelet-activating factor (PAF) receptor antagonist. These results suggest LPC exerts a specific Ca2+ signaling. The sustained elevation reflected the cell lysis. Furthermore, we confirmed its pathway in a more specific manner using cloned PAF receptors expressed in Chinese hamster ovary cells. LPC induced an elevation of [Ca2+]i in a concentration-dependent manner only when the PAF receptor had been expressed, and the elevation of [Ca2+]i was blocked by WEB-2086. Taken together, LPC transduces Ca2+ signaling via the PAF receptor. Activation of the PAF receptor by LPC may indicate its novel important role in the pathogenesis of atherosclerosis.

Mechanisms by Which Elevated Intracellular Calcium Induces S49 Cell Membranes to Become Susceptible to the Action of Secretory Phospholipase A2

“…First, the concentration of lyso-PPC required for the effect was similar to or lower than that required for a variety of biochemical and physiological effects of the lipid reported for other cells and tissues (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Second, as is true for other reported biochemical effects of lyso-PPC (18,24), there was a structural specificity for the phenomenon (see Fig.…”

“…Nevertheless, many recent investigations have explored potential pathological and physiological effects of the lipid such as participation in certain inflammatory conditions (8,11,12), atherosclerosis (13,14), ischemia (15), and regulation of smooth muscle (16,17). On a biochemical scale, lysolecithin has been reported to regulate protein kinase C (18) and phospholipase D activities (19), cellular calcium concentration (20,21), gene expression (22,23), hormone secretion (24), and cation currents (25,26).…”

Sphingosylphosphorylcholine and Lysophosphatidylcholine Are Ligands for the G Protein-coupled Receptor GPR4

“…On the other hand, evidence has been accumulating to support the notion that, at low concentrations, LPC acts through membrane receptors: (a) at relatively low concentrations (Յ10 M), LPC exerts cell-specific effects; (b) LPC increases intracellular Ca 2ϩ concentration in association with production of inositol phosphates; and (c) these actions of LPC are markedly inhibited by treatment of the cells with PTX and U73122 (36). Some LPC effects are believed to be mediated through the PAF receptor in various cell types, reflected by their partial sensitivity to PAF receptor antagonists (WEB-2170, WEB-2086, and CV-6209) (21,22,37,38). We have shown in the present study, however, that intracellular calcium increase and receptor internalization induced by LPC are dependent on the expression of GPR4 and are insensitive to the PAF receptor antagonists, BN52021, WEB-2071, and WEB-2086.…”

Lysophosphatidylcholine is a natural adjuvant that initiates cellular immune responses

“…It stimulates the expression of growth factor and adhesion molecules by endothelial cells [17][18][19] as well as their production of monocyte chemoattractant protein-1 [20]. LPC can activate monocytes and macrophages [21][22][23][24][25] and is one of the intracellular mediators required in the cytotoxic response of human NK cells to tumour cells [26]. After intracutaneous injection in humans, LPC induces a local inflammation and leukocyte accumulation at the site of injection [27].…”