Proinflammatory Macrophage-activating Properties of the Novel Phospholipid Diacylglycerol Pyrophosphate

Abstract

We have found that the novel phospholipid diacylglycerol pyrophosphate (DGPP), identified in bacteria, yeast, and plants, but not in mammalian cells, is able to potently activate macrophages for enhanced secretion of arachidonate metabolites, a key event in the immunoinflammatory response of leukocytes. Macrophage responses to DGPP are specific and are not mediated by its conversion into other putative lipid mediators such as phosphatidic acid, lysophosphatidic acid, or diacylglycerol. The responses to DGPP are compatible with a receptor-recognition event because they are blocked by suramin. Intracellular signaling initiated by DGPP includes phosphorylation and activation of the Group IV cytosolic phospholipase A 2 and of the extracellular-signal regulated p42 mitogen-activated protein kinase (MAPK) and p44 MAPK, and membrane translocation of the protein kinase C isoenzymes ␣, ⑀, ␦. These results establish DGPP as a novel macrophage-activating factor and suggest a potential role for this compound in triggering homeostatic cellular responses.

Regulation of the Saccharomyces cerevisiae DPP1-encoded Diacylglycerol Pyrophosphate Phosphatase by Zinc

“…Exogenous DGPP augments secretion of prostaglandins in mouse macrophages (10). This occurs by a mechanism that involves the activation of cytosolic phospholipase A 2 via the mitogen-activated protein kinase pathway, an important event in the immunoinflammatory response of leukocytes (10). The accumulation of DGPP in plants is short-lived (9); it is rapidly converted to PA and then to DG (11), consistent with the reactions catalyzed by yeast DGPP phosphatase (2).…”

“…For these experiments, we used dioctanoyl DGPP because of its solubility in aqueous solutions. Dioctanoyl DGPP is enzymatically active when employed as a substrate for pure DGPP phosphatase (10). The addition of DGPP to a 50 M 4-(2-pyridylazo)resorcinol, 100 M ZnCl 2 mixture resulted in a dose-dependent decrease in absorbance at 500 nm, indicating the formation of DGPP-zinc complexes (data not shown).…”

“…Metabolic labeling studies with plants, where DGPP was first discovered (3), show that DGPP accumulates upon G protein activation (7) and upon hyperosmotic stress (8,9). Exogenous DGPP augments secretion of prostaglandins in mouse macrophages (10). This occurs by a mechanism that involves the activation of cytosolic phospholipase A 2 via the mitogen-activated protein kinase pathway, an important event in the immunoinflammatory response of leukocytes (10).…”

Subcellular Localization and Role of Lipin-1 in Human Macrophages

“…For example, during IgG-mediated phagocytosis by human monocytes, activation of DAG-dependent forms of protein kinase C precedes AA release (65). If protein kinase C or related kinases mediate the DAG effect on cPLA 2 a, this would probably be an indirect effect, for example, via the MAPK pathway (66)(67)(68). In this regard, we have recently described the JNK-dependent phosphorylation activation of cPLA 2 a in human monocytederived macrophages (39).…”

Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase

“…DGPP phosphatase is present in bacteria, and DGPP and DGPP phosphatase have critical signaling functions in plants (170). Although DGPP has not been identified in mammalian tissues, exogenous DGPP activates arachidonate secretion by mouse macrophages (9) and DGPP antagonizes LPA 3 and, to a lesser extent, LPA 1 receptor interactions (66,245). It is recognized that DGPP is hydrolyzed by LPP (52,107), but this does not preclude expression of a separate DGPP phosphatase activity as occurs in yeast.…”