Premium
A Novel Polyisoprenyl Phosphate Signaling Cascade in Human Neutrophils
Author(s) -
LEVY BRUCE D.,
SERHAN CHARLES N.
Publication year - 2000
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2000.tb06539.x
Subject(s) - lipoxin , microbiology and biotechnology , receptor , phospholipase d , inflammation , signal transduction , g protein coupled receptor , proinflammatory cytokine , lipid signaling , leukotriene b4 , formyl peptide receptor , superoxide , chemistry , intracellular , proto oncogene tyrosine protein kinase src , downregulation and upregulation , eicosanoid , biochemistry , chemotaxis , biology , enzyme , immunology , arachidonic acid , gene
A bstract : 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 “proinflammatory” (leukotriene B 4 ), and “anti‐inflammatory” (aspirin‐triggered lipoxin A 4 ) ligands. Activation of the leukotriene B 4 receptor initiated a rapid (within seconds) decrement in presqualene diphosphate (PSDP), activation of PLD and production of superoxide anions. This contrasts with activation of the LXA 4 receptor by an aspirin‐triggered lipoxin A 4 mimetic that before leukotriene B 4 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‐targeted interactions controlling intracellular responses relevant in inflammation.