Biosynthesis of Platelet-activating Factor (PAF) in Human Polymorphonuclear Leucocytes. The Role of Lyso-PAF Disposal and Free Arachidonic Acid

Overview

Journal Biochem J

Specialty Biochemistry

Date 1990 May 15

PMID 1693077

Citations 7

Authors

M C Garcia

M A Gijon

C Garcia

M L Nieto

M Sanchez Crespo

Affiliations

Soon will be listed here.

Abstract

Theophylline and 1-methyl-3-isobutylxanthine (MIX), compounds that block eicosanoid formation and modulate phospholipase A2 activity, inhibited in a dose-dependent manner the formation of both leukotriene B4 (LTB4) and platelet-activating factor (PAF) by human polymorphonuclear leucocytes (PMN) in response to ionophore A23187. Theophylline and MIX lacked any inhibitory effect on acetyl-CoA: lyso-PAF acetyltransferase activity, which is the rate-limiting step for PAF biosynthesis in PMN. The effect of theophylline and MIX on PAF formation could be reversed by incubating the cells in the presence of 1-10 microM exogenous lyso-PAF. Incubation of PMN homogenates in the presence of unsaturated non-esterified fatty acids resulted in dose-dependent inhibition of the acetyltransferase. This effect was linked to the presence of a free carboxyl group, since both arachidonic acid methyl ester and palmitoyl-arachidonoyl phosphatidylcholine lacked inhibitory activity. This inhibitory effect was also dependent on the number of double bonds, since arachidonic acid (C20:4) and eicosapentaenoic acid (C20:5) displayed maximal effect. Kinetic analysis showed that the effect of arachidonic acid was consistent with competitive inhibition, with a Ki value of about 19 microM. Oxidative metabolites of arachidonic acid showed a lesser inhibitory effect with the following order of potency: arachidonic acid greater than 15-HETE (15-hydroxy-6,8,11,14-eicosatetraenoic acid) greater than LTB4 greater than 5-HETE (5-hydroxy-6,8,11,14-eicosatetraenoic acid) greater than lipoxin A4. Examination of enzymes involved in CoA-dependent acylation revealed a low activity of both arachidonoyl-CoA synthetase and arachidonoyl-CoA: lyso-PAF arachidonoyltransferase. These data indicate a strong influence on PAF biosynthesis of the products of the phospholipase A2 reaction, with lyso-PAF disposal being a critical event for PAF formation, and unsaturated fatty acids acting as feed-back inhibitors. The conversion of arachidonic acid via oxidative metabolism into less active inhibitors of acetyl-CoA:lyso-PAF acetyltransferase seems to be an additional mechanism of modulation of this enzyme activity, linked to the function of lipoxygenases. Finally, the enzyme activities involved in arachidonoyl-CoA-dependent acylation of lyso-PAF show a low efficiency in capturing arachidonic acid.

Citing Articles

Cooperative role of endogenous leucotrienes and platelet-activating factor in ischaemia-reperfusion-mediated tissue injury.

Bitencourt C, Bessi V, Huynh D, Menard L, Lefebvre J, Levesque T J Cell Mol Med. 2013; 17(12):1554-65.

PMID: 24373549 PMC: 3914641. DOI: 10.1111/jcmm.12118.

Involvement of endogenous leukotriene B4 and platelet-activating factor in polymorphonuclear leucocyte recruitment to dermal inflammatory sites in rats.

Belanger C, Elimam H, Lefebvre J, Borgeat P, Marleau S Immunology. 2008; 124(3):295-303.

PMID: 18217950 PMC: 2440823. DOI: 10.1111/j.1365-2567.2007.02767.x.

Platelet-activating factor: the biosynthetic and catabolic enzymes.

Snyder F Biochem J. 1995; 305 ( Pt 3):689-705.

PMID: 7848265 PMC: 1136314. DOI: 10.1042/bj3050689.

Metabolic processing of PAF.

Snyder F Clin Rev Allergy. 1994; 12(4):309-27.

PMID: 7743460 DOI: 10.1007/BF02802298.

Metabolism of platelet-activating factor in human haematopoietic cell lines. Differences between myeloid and lymphoid cells.

Garcia M, Garcia C, Gijon M, Mollinedo F, Sanchez Crespo M Biochem J. 1991; 273 ( Pt 3):573-8.

PMID: 1847616 PMC: 1149801. DOI: 10.1042/bj2730573.

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