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 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
Jiawei
J
Department of Cell Biology, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
Yang
Lili
L
Foulks
Jason M
JM
Weyrich
Andrew S
AS
Marathe
Gopal K
GK
McIntyre
Thomas M
TM
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000378:metabolism*; D001095:Arachidonic Acids / Q000494:pharmacology; D004950:Esterases / Q000037:antagonists & inhibitors; D006801:Humans; D008041:Linoleic Acids; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D063066:Organofluorophosphonates; D063065:Organophosphonates / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000096:biosynthesis* / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology
D001095:Arachidonic Acids; D008041:Linoleic Acids; D063066:Organofluorophosphonates; D063065:Organophosphonates; D010972:Platelet Activating Factor; D013450:Sulfones; C104810:methyl arachidonylfluorophosphonate; C525109:methyl linolenoylfluorophosphonate; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; D004950:Esterases; C022635:serine esterase; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase