A novel polyisoprenyl phosphate signaling cascade in human neutrophils.
Activation of neutrophil (PMN) surface receptors can evoke inflammation and tissue injury via aberrant release of excess effectors. The molecular mechanisms involved in host protection and control of PMN responses have yet to be defined. As Billah and coworkers (1989), and Exton (1997), for example, have pointed out, phospholipase D (PLD) signaling is known to play a pivotal role in PMN activation. Here, we determined the relationship between polyisoprenyl phosphate (PIPP) remodeling and PLD signaling and their impact in activation of PMN receptors by "pro-inflammatory" (leukotriene B4), and "anti-inflammatory" (aspirin-triggered lipoxinA4) ligands. Activation of the leukotriene B4 receptor initiated a rapid (within seconds) decrement in presqualene disphosphate (PSDP), activation of PLD and production of superoxide anions. This contrasts with activation of the LXA4 receptor by an aspirin-triggered lipoxin A4 mimetic that before leukotriene B4 gave an inverse relationship with rapidly increasing PSDP levels, and inhibition of both PLD activity and superoxide generation. PSDP proved to be a potent and direct-acting inhibitor of PLD (rhPLD1b:Ki = 5.9 nM), a property not shared by structurally related endogenous lipids. This PIPP also interacted with Src homology domains, selectively targeting SH2 and not SH3 domains. These results indicate a role for ligand-driven rapid PIPP remodeling as an early switch and "stop" signaling event that controls PMN. Moreover, they indicate that PSDP directly down-regulates PMN signaling events via select protein-target interactions controlling intracellular responses relevant in inflammation.
Levy
B D
BD
Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115 USA.
Serhan
C N
CN
D000818:Animals; D004789:Enzyme Activation; D006801:Humans; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism*; D010739:Phospholipase D / Q000378:metabolism; D010944:Plants / Q000201:enzymology; D011106:Polyisoprenyl Phosphates / Q000378:metabolism*; D015398:Signal Transduction; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism; D018909:src Homology Domains
D011106:Polyisoprenyl Phosphates; D013481:Superoxides; D007975:Leukotriene B4; D010739:Phospholipase D