Lysophosphatidic acid is a major serum noncytokine survival factor for murine macrophages which acts via the phosphatidylinositol 3-kinase signaling pathway.
Lysophosphatidic acid (LPA) is the smallest and structurally simplest of all the glycerophospholipids. It occurs normally in serum and binds with high affinity to albumin, while retaining its biological activity. The effects of LPA are pleiotropic and range from mitogenesis to stress fiber formation. We show a novel role for LPA: as a macrophage survival factor with potency equivalent to serum. Administration of LPA protects macrophages from apoptosis induced by serum deprivation, and protection is equivalent to that with conventional survival factors such as macrophage colony stimulating factor. The ability of LPA to act as a survival factor is mediated by the lipid kinase phosphatidylinositol 3-kinase (PI3K), since LPA activated both the p85-p110 and p110gamma isoforms of PI3K and macrophage survival was blocked completely by wortmannin or LY294002, two mechanistically dissimilar inhibitors of PI3K. pp70(s6k), a downstream kinase activated by PI3K, also contributes to survival, because inhibitors of pp70(s6k), such as rapamycin, blocked macrophage survival in the presence of LPA. Modified forms of LPA and phospholipids, such as phosphatidylcholine and phosphatidylethanolamine, had no survival effect, thereby showing the specificity of LPA. These results show that LPA acts as a potent macrophage survival factor. Based on striking similarities between our LPA and serum data, we suggest that LPA is a major noncytokine survival factor in serum.
Renal Section, Department of Medicine, Boston Medical Center, Boston, Massachusetts 02118, USA.
J S
JS
Koh
W
W
Lieberthal
S
S
Heydrick
J S
JS
Levine
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D008246:Lysophospholipids / Q000097:blood / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011090:Polyenes / Q000494:pharmacology; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus; D013498:Suramin / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D016895:Culture Media, Serum-Free; D008246:Lysophospholipids; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011090:Polyenes; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus; D013498:Suramin; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one