Cytosolic phospholipase A2: Biochemical properties and physiological roles

Shimizu, Takao; Ohto, Takayo; Kita, Yoshiaki

doi:10.1080/15216540600702289

Cited by 84 publications

(57 citation statements)

References 29 publications

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“…Released AA is further converted into prostaglandins (PGs), leukotrienes (LTs), lipoxins, and hydroxy-eicosatetraenoic acids (HETEs), collectively termed eicosanoids, by cyclooxygenases (COXs), lipoxygenases (LOs), and terminal enzymes (8). Involvement of eicosanoids and related lipid mediators has been reported in EAE, collagen-induced arthritis, and other immunological disorders (6,7,9). Previously, we and others clearly demonstrated the importance of cPLA 2 ␣ in EAE pathology by genetically and pharmacologically ablated mouse studies (10)(11)(12).…”

Section: Studies Of Experimental Autoimmune Encephalomyelitis (Eae) mentioning

confidence: 99%

Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis

Kihara

Matsushita

Kita

et al. 2009

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

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123

107

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The arachidonic acid (AA) cascade produces eicosanoids, such as prostaglandins (PGs), that regulate physiological and pathological functions. Although various nonsteroidal anti-inflammatory drugs have been developed, blocking upstream components (cyclooxygenase-1 and -2) of the AA cascade leads to severe side effects, including gastrointestinal ulcers and cardiovascular events, respectively, due to the complexity of the AA cascade. Here, using an AA cascade-targeted lipidomics approach, we report that microsomal PGE synthase 1 (mPGES-1) plays a key role in experimental autoimmune encephalomyelitis (EAE). Eicosanoids (mainly PGD 2) are produced constitutively in the spinal cord of naive mice. However, in EAE lesions, the PGE 2 pathway is favored and the PGD2, PGI2, and 5-lipoxygenase pathways are attenuated. Furthermore, mPGES-1 ؊/؊ mice showed less severe symptoms of EAE and lower production of IL-17 and IFN-␥ than mPGES-1 ؉/؉ mice. Expression of PGE2 receptors (EP1, EP2, and EP4) was elevated in EAE lesions and correlated with clinical symptoms. Immunohistochemistry on central nervous systems of EAE mice and multiple sclerosis (MS) patients revealed overt expression of mPGES-1 protein in microglia/macrophages. Thus, the mPGES-1-PGE 2-EPs axis of the AA cascade may exacerbate EAE pathology. Our findings have important implications for the design of therapies for MS.autoimmunity ͉ demyelination ͉ lipid mediator ͉ mass spectrometry ͉ Th17

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Section: Studies Of Experimental Autoimmune Encephalomyelitis (Eae) mentioning

confidence: 99%

Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis

Kihara

Matsushita

Kita

et al. 2009

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

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123

107

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“…PAF synthesis induced by extracellular signals has been reported in murine peritoneal cells stimulated by calcium ionophore (7) or by PAF (8), in human eosinophils stimulated by fMet-Leu-Phe (9), in human neutrophils stimulated by acid stress (10), and in murine peritoneal macrophages stimulated by lipopolysaccharide (LPS) (11). In the remodeling pathway, the precursor of PAF, 1-Oalkyl-sn-glycero-3-phosphocholine (lyso-PAF), is synthesized from 1-O-alkyl-2-arachidonoyl-sn-glycero-3-phosphocholine (1-alkyl-phosphatidylcholine; PC) by the action of phospholipase A 2 (2,4,12,13). Subsequently, lyso-PAF is converted to PAF by acetyl-CoA:lyso-PAF acetyltransferase (lyso-PAF acetyltransferase) (EC 2.3.1.67) (14).…”

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confidence: 99%

A Single Enzyme Catalyzes Both Platelet-activating Factor Production and Membrane Biogenesis of Inflammatory Cells

Shindou¹,

Hishikawa²,

Nakanishi

et al. 2007

Journal of Biological Chemistry

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220

239

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Platelet-activating factor (PAF) is a potent proinflammatory lipid mediator eliciting a variety of cellular functions. Lipid mediators, including PAF are produced from membrane phospholipids by enzymatic cascades. Although a G protein-coupled PAF receptor and degradation enzymes have been cloned and characterized, the PAF biosynthetic enzyme, aceyl-CoA:lyso-PAF acetyltransferase, has not been identified. Here, we cloned lyso-PAF acetyltransferase, which is critical in stimulusdependent formation of PAF. The enzyme is a 60-kDa microsomal protein with three putative membrane-spanning domains. The enzyme was induced by bacterial endotoxin (lipopolysaccharide), which was suppressed by dexamethasone treatment. Surprisingly, the enzyme catalyzed not only biosynthesis of PAF from lyso-PAF but also incorporation of arachidonoyl-CoA to produce PAF precursor membrane glycerophospholipids (lysophosphatidylcholine acyltransferase activity). Under resting conditions, the enzyme prefers arachidonoyl-CoA and contributes to membrane biogenesis. Upon acute inflammatory stimulation with lipopolysaccharide, the activated enzyme utilizes acetyl-CoA more efficiently and produces PAF. Thus, our findings provide a novel concept that a single enzyme catalyzes membrane biogenesis of inflammatory cells while producing a prophlogistic mediator in response to external stimuli.Platelet-activating factor (PAF 3 ; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a phospholipid mediator that activates a G protein-coupled receptor (1-3) and results in pleiotropic and potent biological effects, including platelet activation, airway constriction, and hypotension (1). PAF is synthesized in various cells and tissues via two distinct pathways, the de novo and remodeling pathways (2, 4, 5), and the latter is regulated by extracellular signals and plays a critical role in stimulus-coupled PAF biosynthesis (2, 4 -6). PAF synthesis induced by extracellular signals has been reported in murine peritoneal cells stimulated by calcium ionophore (7) or by PAF (8), in human eosinophils stimulated by fMet-Leu-Phe (9), in human neutrophils stimulated by acid stress (10), and in murine peritoneal macrophages stimulated by lipopolysaccharide (LPS) (11). In the remodeling pathway, the precursor of PAF, 1-Oalkyl-sn-glycero-3-phosphocholine (lyso-PAF), is synthesized from 1-O-alkyl-2-arachidonoyl-sn-glycero-3-phosphocholine (1-alkyl-phosphatidylcholine; PC) by the action of phospholipase A 2 (2, 4, 12, 13). Subsequently, lyso-PAF is converted to PAF by acetyl-CoA:lyso-PAF acetyltransferase (lyso-PAF acetyltransferase) (EC 2.3.1.67) (14). PAF is then rapidly degraded to lyso-PAF by PAF acetylhydrolases (15). Alternatively, lyso-PAF is again transformed into PC by the action of lysophosphatidylcholine (LPC) acyltransferase (2.3.1.23) (16).A G protein-coupled PAF receptor was cloned in our laboratory (17), and PAF acetylhydrolases have been cloned and characterized by others (18,19). Lyso-PAF acetyltransferase was initially demonstrated and partially characterized by ...

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“…One of the mechanisms that could bring about a hibernation-responsive stable change in cPLA 2 activity and K m is a change in the phosphorylation state of the enzyme. Alpha-cPLA 2 can be phosphorylated by several serine/threonine kinases and tyrosine kinases [8]. In other species, phosphorylation of S 505 is known to cause an increase in cPLA 2 activity [25].…”

Section: Discussionmentioning

confidence: 99%

“…The source of S 505 and S 727 phosphorylation is also controversial but these two residues are conserved and have a direct impact on the activity of α-cPLA 2 . In different systems, the source of S 505 phosphorylation has been linked to the mitogenactivated protein kinase (MAPK) family [8,9] whereas S 727 phosphorylation is linked to protein kinases A or C in some systems but this phosphorylation is not necessarily correlated with an increase in activity [6]. Calcium is also required for the translocation of α-cPLA 2 to the membrane [10].…”

Section: Introductionmentioning

confidence: 99%

“…All have high sequence homology, but differ in their selectivity for arachidonic acid [5], the alpha isozyme being the most selective. Recent analysis of the mouse genome has also identified the presence of genes for a further three isozymes of cPLA 2 although little else is known about them to date [8]. α-cPLA 2 is the best-studied and is subject to posttranslational modification by phosphorylation on up to four serine residues: S 437 , S 454 , S 505 , and S 727 .…”

Section: Introductionmentioning

confidence: 99%

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Cytosolic phospholipase A2 regulation in the hibernating thirteen-lined ground squirrel

Woods

Storey

2007

Cellular and Molecular Biology Letters

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Cytosolic calcium-dependent phospholipase A 2 (cPLA 2 ) has multiple roles including production of arachidonic acid (a key player in cellular signaling pathways) and membrane remodeling. Additionally, since catabolism of arachidonic acid generates free radicals, the enzyme is also implicated in ischemic injury to mammalian organs. Regulation of cPLA 2 could be important in the suppression and prioritization of cellular pathways in animals that undergo reversible transitions into hypometabolic states. The present study examines the responses and regulation of cPLA 2 in skeletal muscle and liver of hibernating thirteen-lined ground squirrels, Spermophilus tridecemlineatus. cPLA 2 activity decreased significantly by 43% in liver during hibernation, compared with euthermic controls, and K m values for arachidonoyl thio-PC substrate fell in both organs during hibernation to 61% in liver and 28% in muscle of the corresponding euthermic value. To determine whether these responses were due to a change in the phosphorylation state of the enzyme, Western blotting was employed using antibodies recognizing phospho-Ser 505 on α-cPLA 2 . The amount of phosphorylated α-cPLA 2 in hibernator liver was just 38% of the value in euthermic liver. Furthermore, incubation of liver extracts under conditions that enhanced protein phosphatase action caused a greater reduction in the detectable amount of phospho-Ser 505 enzyme content in euthermic, versus hibernator, extracts. The data are consistent with a suppression of cPLA 2 function during torpor via enzyme dephosphorylation, an action that may contribute to the welldeveloped ischemia tolerance and lack of oxidative damage found in hibernating species over cycles of torpor and arousal.

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Cytosolic phospholipase A2: Biochemical properties and physiological roles

Cited by 84 publications

References 29 publications

Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis

Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis

A Single Enzyme Catalyzes Both Platelet-activating Factor Production and Membrane Biogenesis of Inflammatory Cells

Cytosolic phospholipase A2 regulation in the hibernating thirteen-lined ground squirrel

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