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 structur-ally simplest of all the glycerophospholipids. It occurs nor-mally 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 for-mation. We show a novel role for LPA: as a macrophage survival factor with potency equivalent to serum. Adminis-tration of LPA protects macrophages from apoptosis in-duced 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 sur-vival factor is mediated by the lipid kinase phosphatidyl-inositol 3-kinase (PI3K), since LPA activated both the p85-p110 and p110 g 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. Modi-fied forms of LPA and phospholipids, such as phosphatidyl-choline and phosphatidylethanolamine, had no survival ef-fect, 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.