Intracellular PAF catabolism by PAF acetylhydrolase counteracts continual PAF synthesis

Stimulated inflammatory cells synthesize platelet- activating factor (PAF), but lysates of these cells show little enhancement in PAF synthase activity. We show that human neutrophils contain intracellular plasma PAF acetylhydrolase (PLA2G7), an enzyme normally secreted by monocytes. The esterase inhibitors methyl arachidonoylfluorophosphonate (MAFP), its linoleoyl homolog, and Pefabloc inhibit plasma PAF acetylhydrolase. All of these inhibitors induced PAF ac- cumulation by quiescent neutrophils and monocytes that was equivalent to agonist stimulation. Agonist stimulation after esterase inhibition did not further increase PAF accu- mulation. PAF acetylhydrolase activity in intact neutrophils was reduced, but not abolished, by agonist stimulation. Erythrocytes, which do not participate in the acute inflam- matory response, inexplicably express the type I PAF acetyl- hydrolase, whose only known substrate is PAF. Inhibition of this enzyme by MAFP caused PAF accumulation by erythro- cytes, which was hemolytic in the absence of PAF acetyl- hydrolase activity. We propose that PAF is continuously synthesized by a nonselective acyltransferase activity(ies) found even in noninflammatory cells as a component of membrane remodeling, which is then selectively and con- tinually degraded by intracellular PAF acetylhydrolase activity to modulate PAF production.—Chen, J., L. Yang, J. M. Foulks, A. S. Weyrich, G. K. Marathe, and T. M. McIntyre. Intracellular PAF catabolism by PAF acetylhydro- lase counteracts continual PAF synthesis. J. Lipid Res. 2007. 48: 2365-2376.