Platelet-activating factor: the biosynthetic and catabolic enzymes

Snyder, Fred

doi:10.1042/bj3050689

Cited by 196 publications

(144 citation statements)

References 200 publications

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“…Because lyso-PAF had been suggested to be a substrate of AGMO (16), it was speculated that this enzyme might limit PAF synthesis in cells (8,11,17). However, the data presented in Fig.…”

Section: Discussionmentioning

confidence: 95%

“…The category of glycerolipids comprising the class of monoradylglycerols that contains the subclass of monoalkylglycerols (i.e., the four species found to be most significantly changed; see above) did not appear to be significantly enriched, because alkylglycerols with side-chain carbon atoms [16][17][18][19][20][21][22] were not yet listed in the version of LIPID MAPS used.…”

Section: Impact Of Agmo Activity Manipulation On Ifn-γ/lps-induced Nimentioning

confidence: 99%

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Tetrahydrobiopterin and alkylglycerol monooxygenase substantially alter the murine macrophage lipidome

Watschinger

Keller

McNeill

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Tetrahydrobiopterin is a cofactor synthesized from GTP with well-known roles in enzymatic nitric oxide synthesis and aromatic amino acid hydroxylation. It is used to treat mild forms of phenylketonuria. Less is known about the role of tetrahydrobiopterin in lipid metabolism, although it is essential for irreversible ether lipid cleavage by alkylglycerol monooxygenase. Here we found intracellular alkylglycerol monooxygenase activity to be an important regulator of alkylglycerol metabolism in intact murine RAW264.7 macrophage-like cells. Alkylglycerol monooxygenase was expressed and active also in primary mouse bone marrowderived monocytes and "alternatively activated" M2 macrophages obtained by interleukin 4 treatment, but almost missing in M1 macrophages obtained by IFN-γ and lipopolysaccharide treatment. The cellular lipidome of RAW264.7 was markedly changed in a parallel way by modulation of alkylglycerol monooxygenase expression and of tetrahydrobiopterin biosynthesis affecting not only various ether lipid species upstream of alkylglycerol monooxygenase but also other more complex lipids including glycosylated ceramides and cardiolipins, which have no direct connection to ether lipid pathways. Alkylglycerol monooxygenase activity manipulation modulated the IFN-γ/lipopolysaccharide-induced expression of inducible nitric oxide synthase, interleukin-1β, and interleukin 1 receptor antagonist but not transforming growth factor β1, suggesting that alkylglycerol monooxygenase activity affects IFN-γ/lipopolysaccharide signaling. Our results demonstrate a central role of tetrahydrobiopterin and alkylglycerol monooxygenase in ether lipid metabolism of murine macrophages and reveal that alteration of alkylglycerol monooxygenase activity has a profound impact on the lipidome also beyond the class of ether lipids. alkylglycerols | lipidomics | macrophages | RAW264.7 | tetrahydrobiopterin

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“…Because lyso-PAF had been suggested to be a substrate of AGMO (16), it was speculated that this enzyme might limit PAF synthesis in cells (8,11,17). However, the data presented in Fig.…”

Section: Discussionmentioning

confidence: 95%

Section: Impact Of Agmo Activity Manipulation On Ifn-γ/lps-induced Nimentioning

confidence: 99%

Tetrahydrobiopterin and alkylglycerol monooxygenase substantially alter the murine macrophage lipidome

Watschinger

Keller

McNeill

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Neutrophils are a major source of PAF in vivo, and two biosynthetic pathways have been proposed for PAF biosynthesis in these cells (37). In the first pathway, a PLA 2 catalyzes the hydrolysis of 1-Oalkyl-2-acyl-phosphatidylcholine yielding lyso-PAF, which is acetylated by acetyl-CoA:1-Oalkyl-2-lyso-phosphatidylcholine acetyltransferase to produce PAF.…”

Section: Role Of Cpla 2 -α In Neutrophil Paf Biosynthesismentioning

confidence: 99%

Cytosolic Phospholipase A2-α Is Necessary for Platelet-activating Factor Biosynthesis, Efficient Neutrophil-mediated Bacterial Killing, and the Innate Immune Response to Pulmonary Infection

Rubin

Downey

Koh

et al. 2005

Journal of Biological Chemistry

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The role of a cytosolic phospholipase A 2 -α (cPLA 2 -α) in neutrophil arachidonic acid release, plateletactivating factor (PAF) biosynthesis, NADPH oxidase activation, and bacterial killing in vitro, and the innate immune response to bacterial infection in vivo was examined. cPLA 2 -α activity was blocked with the specific cPLA 2 -α inhibitor, Pyrrolidine-1 (human cells), or by cPLA 2 -α gene disruption (mice). cPLA 2 -α inhibition or gene disruption led to complete suppression of neutrophil arachidonate release and PAF biosynthesis but had no effect on neutrophil NADPH oxidase activation, FcγII/III or CD11b surface expression, primary or secondary granule secretion, or phagocytosis of Escherichia coli in vitro. In contrast, cPLA 2 -α inhibition or gene disruption diminished neutrophil-mediated E. coli killing in vitro, which was partially rescued by exogenous arachidonic acid or PAF but not leukotriene B 4 . Following intratracheal inoculation with live E. coli in vivo, pulmonary PAF biosynthesis, inflammatory cell infiltration, and clearance of E. coli were attenuated in cPLA 2 -α (−/−) mice compared with wild type littermates. These studies identify a novel * This work was supported by grants from The Physicians of Ontario through The P.S.I. Foundation (Grant 01-12 (to B. B. R.) and 98-049

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“…1 The multiplex quantification system allows high-throughput comprehensive analysis of PGs, LTs, HETEs, and PAF. In this paper, we report a pathwayoriented profiling of lipid mediator production in mouse peritoneal macrophages.…”

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confidence: 99%

Pathway-oriented profiling of lipid mediators in macrophages

Kita

Takahashi

Uozumi

et al. 2005

Biochemical and Biophysical Research Communications

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Macrophages produce various kinds of lipid mediators including eicosanoids and platelet-activating factor. Since they are produced from common precursors, arachidonic acid-containing phospholipids, regulations of metabolic pathways underlie the patterning of lipid mediator production. Here, we report a pathway-oriented profiling strategy of lipid mediators by a newly developed multiplex quantification system. We profiled mouse peritoneal macrophages in different activation states. The analysis of kinetics revealed the differences in the production time course of various lipid mediators, which also differed by the macrophage types. Scatterplot matrix analysis of the inhibitor study revealed correlations of lipid mediator species. The changes of these correlations provided estimates on the effects of lipopolysaccharide priming. We also found a highly linked production of 11-hydroxyeicosatetraenoic acid and prostaglandin E 2 , implying the in vivo property of cyclooxygenasemediated 11-hydroxyeicosatetraenoic acid production. The present approach will serve as a strategy for understanding the regulatory mechanism of lipid mediator production.

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Platelet-activating factor: the biosynthetic and catabolic enzymes

Cited by 196 publications

References 200 publications

Tetrahydrobiopterin and alkylglycerol monooxygenase substantially alter the murine macrophage lipidome

Tetrahydrobiopterin and alkylglycerol monooxygenase substantially alter the murine macrophage lipidome

Cytosolic Phospholipase A2-α Is Necessary for Platelet-activating Factor Biosynthesis, Efficient Neutrophil-mediated Bacterial Killing, and the Innate Immune Response to Pulmonary Infection

Pathway-oriented profiling of lipid mediators in macrophages

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