Intracellular PAF catabolism by PAF acetylhydrolase counteracts continual PAF synthesis

Abstract

Stimulated inflammatory cells synthesize plateletactivating 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.-Chen, J., L. Yang, J. M. Foulks, A. S. Weyrich, G. K. Marathe, and T. M. McIntyre. Intracellular PAF catabolism by PAF acetylhydrolase counteracts continual PAF synthesis. J. Lipid Res.

PAF-acetylhydrolase expressed during megakaryocyte differentiation inactivates PAF-like lipids

“…Third, the specific activity of the plasma PAF-AH isoform is 100-fold higher than either of the type 1 enzymes. 47 Finally, Pefabloc quenches PAF-AH activity allowing PAF-like lipids to accumulate, and previous studies have demonstrated that Pefabloc inhibits the plasma PAF-AH 40 but not the type 1 enzymes. 47 Inhibition of endogenous PAF-AH activity in megakaryocytes allowed PAF-like lipids, but not PAF, to accumulate in treated cells.…”

“…47 Finally, Pefabloc quenches PAF-AH activity allowing PAF-like lipids to accumulate, and previous studies have demonstrated that Pefabloc inhibits the plasma PAF-AH 40 but not the type 1 enzymes. 47 Inhibition of endogenous PAF-AH activity in megakaryocytes allowed PAF-like lipids, but not PAF, to accumulate in treated cells. Accumulation of PAF-like lipids in megakaryocytes contrasts neutrophils where inhibition of PAF-AH has been linked to the synthesis of PAF.…”

“…Accumulation of PAF-like lipids in megakaryocytes contrasts neutrophils where inhibition of PAF-AH has been linked to the synthesis of PAF. 47 Megakaryocyte-derived PAF-like lipids activate the PAFR on neutrophils and megakaryocytes themselves. This suggests that dysregulated accumulation of PAF-like lipids may induce both autocrine and paracrine signaling events in the bone marrow milieu in hematopoietic cells that express a functional PAFR signaling system.…”

The emerging roles of PAF acetylhydrolase

“…Recent studies have revealed that PAF synthesis takes place in the absence of cellular activation (48). This con-tinual PAF synthesis and degradation occurs not only in cells of the innate immune system but also in erythrocytes.…”

“…Importantly, the amount of PAF accumulated by neutrophils in this way is equivalent to that induced by agonist stimulation. Mammalian cells silence this potential for basal PAF signaling through the enzymatic activity of plasma PAF-AH retained in the intracellular compartment, as demonstrated by immunoblot and inhibitor studies (48).…”