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J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M700325-JLR200 on August 10, 2007

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Journal of Lipid Research, Vol. 48, 2365-2376, November 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Intracellular PAF catabolism by PAF acetylhydrolase counteracts continual PAF synthesisboxs

Jiawei Chen*, Lili Yang*, Jason M. Foulks{dagger}, Andrew S. Weyrich§, Gopal K. Marathe1,* and Thomas M. McIntyre1,*,{dagger}

* Department of Cell Biology, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44195
{dagger} Department of Experimental Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112
§ Departments of Internal Medicine and Human Molecular Biology and Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112

boxs The online version of this article (available at http://www.jlr.org) contains supplemental data in the form of two figures and one table.

Published, JLR Papers in Press, August 10, 2007.

1 To whom correspondence should be addressed. e-mail: marathg{at}ccf.org (G.K.M.); mcintyt{at}ccf.org (T.M.M.)

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 accumulation by quiescent neutrophils and monocytes that was equivalent to agonist stimulation. Agonist stimulation after esterase inhibition did not further increase PAF accumulation. PAF acetylhydrolase activity in intact neutrophils was reduced, but not abolished, by agonist stimulation. Erythrocytes, which do not participate in the acute inflammatory response, inexplicably express the type I PAF acetylhydrolase, whose only known substrate is PAF. Inhibition of this enzyme by MAFP caused PAF accumulation by erythrocytes, which was hemolytic in the absence of PAF acetylhydrolase 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 continually degraded by intracellular PAF acetylhydrolase activity to modulate PAF production.

Supplementary key words platelet-activating factor • recycling • methyl arachidonoylfluorophosphonate • Pefabloc • phospholipase • lipoprotein-associated phospholipase A2 • hemolysis

Abbreviations: LPS, lipopolysaccharide; MAFP, methyl arachidonoylfluorophosphonate; MLnFP, methyl linolenoylfluorophosphonate; PAF, platelet-activating factor; PMN, neutrophils; SIN-1, 3-morpholinosydnonimine; TNF-{alpha}, tumor necrosis factor-{alpha}


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