Anti-inflammatory properties of a platelet-activating factor acetylhydrolase.
Platelet-activating factor (PAF) is a potent pro-inflammatory phospholipid that activates cells involved in inflammation. The biological activity of PAF depends on its structural features, namely an ether linkage at the sn-1 position and an acetate group at the sn-2 position. The actions of PAF are abolished by hydrolysis of the acetyl residue, a reaction catalysed by PAF acetylhydrolase. There are at least two forms of this enzyme--one intracellular and another that circulates in plasma and is likely to regulate inflammation. Here we report the molecular cloning and characterization of the human plasma PAF acetylhydrolase. The unique sequence contains a Gly-Xaa-Ser-Xaa-Gly motif commonly found in lipases. Recombinant PAF acetylhydrolase has the substrate specificity and lipoprotein association of the native enzyme, and blocks inflammation in vivo: it markedly decreases vascular leakage in pleurisy and paw oedema, suggesting that PAF acetylhydrolase might be a useful therapy for severe acute inflammation.
Tjoelker
L W
LW
ICOS Corporation, Bothell, Washington 98021, USA.
Wilder
C
C
Eberhardt
C
C
Stafforini
D M
DM
Dietsch
G
G
Schimpf
B
B
Hooper
S
S
Le Trong
H
H
Cousens
L S
LS
Zimmerman
G A
GA
Yamada
Y
Y
McIntyre
T M
TM
Prescott
S M
SM
Gray
P W
PW
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000378:metabolism; D008969:Molecular Sequence Data; D010741:Phospholipases A / Q000235:genetics* / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D010972:Platelet Activating Factor; D011994:Recombinant Proteins; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase