Phosphatidic Acid Is a Leukocyte Chemoattractant That Acts through S6 Kinase Signaling

摘要: Phosphatidic acid (PA) is a pleiotropic lipid second messenger in mammalian cells. We report here that extracellular PA acts as leukocyte chemoattractant, membrane-soluble dioleoyl-PA (DOPA) elicits actin polymerization and chemotaxis of human neutrophils differentiated proleukemic HL-60 show the mechanism for this involves S6 kinase (S6K) signaling enzyme. Chemotaxis was inhibited >90% by S6K inhibitors rapamycin bisindolylmaleimide S6K1 silencing using double-stranded RNA. However, it only moderately (∼30%) mTOR siRNA, indicating presence an mTOR-independent S6K. Exogenous led to robust time- dose-dependent increases enzymatic activity Thr421/Ser424 phosphorylation, further supporting PA/S6K connection. also investigated whether intracellular production affects cell migration. Overexpression phospholipase D2 (PLD2) and, lesser extent, PLD1, resulted elevation both chemokinesis, whereas PLD inhibitory. Because lipase-inactive PLD2 mutants K444R K758R neither activated nor induced chemotaxis, needed form Lastly, we demonstrated connection between PA. Using enhanced green fluorescent protein-derived sensor (pEGFP-Spo20PABD), showed exogenous or generated situ bacterial (Streptomyces chromofuscus) enters accumulates vesicle-like cytoplasmic structures. In summary, discovery chemoattractant via entry activation mediate cytoskeletal required immune function these