Opposing effects of platelet-activating factor and lyso-platelet-activating factor on neutrophil and platelet activation

Emily J. Welch, Ram P. Naikawadi, Zhenyu Li, Phoebe Lin, Satoshi Ishii, Takao Shimizu, Chinnaswamy Tiruppathi, Xiaoping Du, Papasani V. Subbaiah, Richard D. Ye

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Platelet-activating factor (PAF) is a potent, bioactive phospholipid that acts on multiple cells and tissues through its G protein-coupled receptor (GPCR). PAF is not stored but is rapidly generated via enzymatic acetylation of the precursor 1-O-hexadecyl-2-hydroxy-sn-glycero-3-phosphocholine (lysoPAF). The bioactivity of PAF is effectively and tightly regulated by PAF acetylhydrolases, which convert PAF back to lysoPAF. Previous studies report that lysoPAF is an inactive precursor and metabolite of PAF. However, lysoPAF has not been carefully studied in its own context. Here we report that lysoPAF has an opposing effect of PAF in the activation of neutrophils and platelets. Whereas PAF potentiates neutrophil NADPH oxidase activation, lysoPAF dose-dependently inhibits this function. Inhibition by lysoPAF is not affected by the use of a PAF receptor antagonist or genetic deletion of the PAF receptor gene. The mechanism of lysoPAF-mediated inhibition of neutrophils involves an elevation in the intracellular cAMP level, and pharmacological blockade of adenylyl cyclase completely reverses the inhibitory effect of lysoPAF. In addition, lysoPAF increases intracellular cAMP levels in platelets and inhibits thrombin-induced platelet aggregation, which can be reversed by inhibition of protein kinase A. These findings identify lysoPAF as a bioactive lipid with opposing functions of PAF and suggest a novel and intrinsic regulatory mechanism for balance of the potent activity of PAF.

Original languageEnglish (US)
Pages (from-to)227-234
Number of pages8
JournalMolecular Pharmacology
Volume75
Issue number1
DOIs
StatePublished - Jan 2009
Externally publishedYes

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Neutrophil Activation
Platelet Activating Factor
Platelet Activation
Neutrophils
O-deacetyl platelet activating factor
Phosphorylcholine
NADPH Oxidase
Acetylation
G-Protein-Coupled Receptors
Cyclic AMP-Dependent Protein Kinases
Platelet Aggregation
Adenylyl Cyclases
Thrombin
Phospholipids
Blood Platelets
Pharmacology

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Opposing effects of platelet-activating factor and lyso-platelet-activating factor on neutrophil and platelet activation. / Welch, Emily J.; Naikawadi, Ram P.; Li, Zhenyu; Lin, Phoebe; Ishii, Satoshi; Shimizu, Takao; Tiruppathi, Chinnaswamy; Du, Xiaoping; Subbaiah, Papasani V.; Ye, Richard D.

In: Molecular Pharmacology, Vol. 75, No. 1, 01.2009, p. 227-234.

Research output: Contribution to journalArticle

Welch, EJ, Naikawadi, RP, Li, Z, Lin, P, Ishii, S, Shimizu, T, Tiruppathi, C, Du, X, Subbaiah, PV & Ye, RD 2009, 'Opposing effects of platelet-activating factor and lyso-platelet-activating factor on neutrophil and platelet activation', Molecular Pharmacology, vol. 75, no. 1, pp. 227-234. https://doi.org/10.1124/mol.108.051003
Welch, Emily J. ; Naikawadi, Ram P. ; Li, Zhenyu ; Lin, Phoebe ; Ishii, Satoshi ; Shimizu, Takao ; Tiruppathi, Chinnaswamy ; Du, Xiaoping ; Subbaiah, Papasani V. ; Ye, Richard D. / Opposing effects of platelet-activating factor and lyso-platelet-activating factor on neutrophil and platelet activation. In: Molecular Pharmacology. 2009 ; Vol. 75, No. 1. pp. 227-234.
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