Polyisoprenyl phosphate (PIPP) signaling regulates phospholipase D activity: a 'stop' signaling switch for aspirin-triggered lipoxin A(4)

It is of wide interest to understand how opposing extracellular signals (po sitive or negative) are translated into intracellular signaling events. Rec eptor-ligand interactions initiate the generation of bioactive lipids by hu man neutrophils (PMN), which serve as signals to orchestrate cellular respo nses important in host defense and inflammation. We recently identified a n ovel polyisoprenyl phosphate (PIPP) signaling pathway and found that one of its components, presqualene diphosphate (PSDP), is a potent negative intra cellular signal in PMN that regulates superoxide anion generation by severa l stimuli, including phosphatidic acid, We determined intracellular PIPP si gnaling by autocoids with opposing actions on PMN: leukotriene B-4 (LTB4), a potent chemoattractant, and lipoxin A(4) (IXA(4)), a 'stop signal' for re cruitment, LTB4 receptor activation initiated a rapid decrease in PSDP leve ls concurrent with activation of PLD and cellular responses. In sharp contr ast, activation of the LXA(4) receptor reversed LTB4-initiated PSDP remodel ing, leading to an accumulation of PSDP and potent inhibition of both PLD a nd superoxide anion generation, Thus, an inverse relationship was establish ed for PSDP levers and PLD activity with two PMN ligands that evoke opposin g responses. In addition, PSDP directly inhibited both isolated human recom binant (K-i = 6 nM) and plant (K-i = 20 nM) PLD, Together, these findings l ink PIPP remodeling to intracellular regulation of PMN function and suggest a role for PIPPs as lipid repressors in signal transduction, a novel mecha nism that may also explain aspirin's suppressive actions in vivo in cell si gnaling.