Role of cytosolic phospholipase A2 in allergic response and parturition

Uozumi, Naonori; Kume, Kazuhiko; Nagase, Takahide; Nakatani, Noriaki; Ishii, Satoshi; Tashiro, Fumi; Komagata, Yoshinori; Maki, Kazushige; Ikuta, Koichi; Ouchi, Yasuyoshi; Miyazaki, Junichi; Shimizu, Takao

doi:10.1038/37622

Cited by 668 publications

(567 citation statements)

References 138 publications

(133 reference statements)

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“…To achieve reduction of LT formation, reasonable targets include PLA 2 enzymes, 5-LO, FLAP, LTA 4 hydrolase and LTC 4 synthase/MAPEGs, with 5-LO being the preferred target. Although experiments in cPLA 2 -deficient mice support the concept that inhibition of PLA 2 enzymes prevents the formation of basically all eicosanoids [66], clinical studies using glucocorticoids that suppress cPLA 2 enzymes proved to be ineffective in reducing the levels of LTs [5].…”

Section: Molecular Pharmacology Of 5-lipoxygenase Inhibitorsmentioning

confidence: 99%

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

Werz¹

2007

Planta Med

149

135

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The biosynthesis of leukotrienes (LTs) is initiated by the transformation of free arachidonic acid to LTA 4 by 5-lipoxygenase (5-LO). Subsequent enzymatic conversion of LTA 4 yields LTB 4 and the cysteinyl-LTs C 4 , D 4 and E 4 . LTs have prominent functions in pathophysiology and are connected to numerous disorders including bronchial asthma, allergic rhinitis, inflammatory bowel and skin diseases, rheumatoid arthritis, cancer, osteoporosis and cardiovascular diseases. Pharmacological and genetic interruption of the 5-LO pathway or blockade of LT receptors, serving as means for intervention with LTs, may be of therapeutic value for certain related disorders. Natural or plant-derived substances were among the first 5-LO inhibitors identified in the early 1980 s. To date, a huge number of diverse plant-derived compounds have been reported to interfere with 5-LO product synthesis. However, many investigations have addressed the efficacy of a given compound solely in cellular test systems and analysis of direct interference with 5-LO has been neglected. In the first part of this review, the biology and molecular pharmacology of the 5-LO pathway is summarized in order to understand its overall regulation and complexity as well as to comprehend the possible points of attack of compounds that eventually lead to inhibition of 5-LO product formation in intact cells. In the second part, natural compounds that interfere with 5-LO product formation are compiled and grouped into structural classes, and the underlying molecular mechanisms and structureactivity relationships are discussed.

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Section: Molecular Pharmacology Of 5-lipoxygenase Inhibitorsmentioning

confidence: 99%

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

Werz¹

2007

Planta Med

149

135

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“…Interestingly, macrophages from mice deficient in cPLA 2 -α produced no prostaglandins or leukotrienes and various disease models have now been studied in these animals [5]. These mice demonstrate reduced fertility and reduced brain injury after cerebral ischaemia [6][7][8]. Three human paralogs of the cPLA 2 -α enzyme have also been identified, termed cPLA 2 -β, cPLA 2 -γ and cPLA 2 -δ [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Polychlorinated biphenyls induce arachidonic acid release in human platelets in a tamoxifen sensitive manner via activation of group IVA cytosolic phospholipase A2-α

Forsell

Olsson

Andersson

et al. 2005

Biochemical Pharmacology

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Polychlorinated biphenyls (PCBs) are stable compounds commonly found in nature as environmental pollutants. PCBs can affect the endocrine function of hormones such as steroid-hormones. Also, PCBs are known to be inducers of arachidonic acid release in various cells. We report, here, the effects of PCBs on eicosanoid formation, arachidonic acid release and cytosolic phospholipase A 2 -α(cPLA 2 -α) activation in human platelets. Ortho-substituted PCBs induced a time and dosedependent release of arachidonic acid and the concomitant formation of 12(S)-hydroxy-5,8-cis-10-trans-14-cis-eicosatetraenoic acid (12-HETE) and 12(S)-hydroxy-5-cis-8,10-transheptadecatrienoic acid (12-HHT) in human platelets. The release of arachidonic acid and the formation of 12-HETE was completely blocked by the cPLA 2 -α inhibitors AACOCF 3 or pyrrolidine-1. PCB-treatment of platelets demonstrated that the cPLA 2 -α protein as well as PLA 2 activity translocated to the membrane fraction, independent of a rise in intracellular Ca 2+ . Furthermore, electrophoretic gel mobility shift analysis of cPLA 2 -α on SDS-PAGE demonstrated a PCB-dependent phosphorylation of cPLA 2 -α. The effects of 17β-estradiol and two structurally unrelated anti-estrogens, nafoxidin and tamoxifen on PCB-induced arachidonic acid release in platelets were also investigated. Both nafoxidin and tamoxifen inhibited PCB-induced arachidonic acid release as well as 12-HETE and 12-HHT formation. Interestingly, platelets incubated with PCBs did not aggregate despite the fact that robust release of arachidonic acid was observed. In summary, these results demonstrate that certain PCBs induce activation of cPLA 2 -α independent of a rise in intracellular calcium and a robust release of arachidonic acid release with resulting eicosanoid formation in human platelets.

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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).…”

mentioning

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

Self Cite

209

230

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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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Role of cytosolic phospholipase A2 in allergic response and parturition

Cited by 668 publications

References 138 publications

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

Polychlorinated biphenyls induce arachidonic acid release in human platelets in a tamoxifen sensitive manner via activation of group IVA cytosolic phospholipase A2-α

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

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