Phospholipase A2 isoforms: a perspective

Chakraborti, Sajal

doi:10.1016/s0898-6568(02)00144-4

Cited by 169 publications

(148 citation statements)

References 257 publications

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“…A number of oxidases and peroxidases act on arachidonate and in so doing, generate oxidants (33,34). These include the cyclooxygenase and lipoxygenase enzyme families (35). Because there is significant redundancy among these enzymes in macrophages we did not attempt to address which specific ones were involved, although 12/15 lipoxygenase is likely to be a major participant.…”

Section: Discussionmentioning

confidence: 99%

TNF-α Inhibits Macrophage Clearance of Apoptotic Cells via Cytosolic Phospholipase A2 and Oxidant-Dependent Mechanisms

McPhillips

Janssen

Ghosh

et al. 2007

The Journal of Immunology

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Removal of apoptotic cells from inflammatory sites is an important step in the resolution of inflammation. Both murine and human macrophages stimulated with TNF-α or directly administered arachidonic acid showed an impaired ability to ingest apoptotic cells (efferocytosis). The inhibition was shown to be due to generation of reactive oxygen species, was blocked with a superoxide dismutase mimetic, MnTBAP, and was mimicked by direct addition of H2O2. To determine the mechanism of TNF-α-stimulated oxidant production, bone marrow-derived macrophages from gp91phox-deficient mice were examined but shown to still produce oxidants and exhibit defective apoptotic cell uptake. In contrast, a specific cytosolic phospholipase A2 inhibitor blocked the oxidant production and reversed the inhibited uptake. The suppressive effect of endogenous or exogenous oxidants on efferocytosis was mediated through activation of the GTPase, Rho. It was reversed in macrophages pretreated with C3 transferase to inactivate Rho or with an inhibitor of Rho kinase. During maturation of human monocyte-derived macrophages, only mature cells exhibited TNF-α-induced suppression of apoptotic cell clearance. The resistance of immature macrophages to such inhibition was shown to result not from defective generation of oxidants, but rather, from lack of response of these cells to the oxidants. Overall, the data suggest that macrophages in a TNF-α- and oxidant-rich inflammatory environment are less able to remove apoptotic cells and, thereby, may contribute to the local intensity of the inflammatory response.

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Section: Discussionmentioning

confidence: 99%

TNF-α Inhibits Macrophage Clearance of Apoptotic Cells via Cytosolic Phospholipase A2 and Oxidant-Dependent Mechanisms

McPhillips

Janssen

Ghosh

et al. 2007

The Journal of Immunology

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“…Polymorphonuclear neutrophils are often the first leukocytes to migrate toward inflammatory lesions where they perform host defense functions such as phagocytosis, The first step in eicosanoid generation is the release of AA from membrane phospholipids by a phospholipase (PL)A 2 enzyme [17], in a Ca 2+ -dependent fashion. In neutrophils, type IV cytosolic (c)PLA 2 has been identified as the preeminent isoform responsible for the mobilization of AA committed for the generation of LTs [18,19], which starts when 5-LO inserts an oxygen molecule at the fifth carbon of unesterified AA forming the hydroperoxyl intermediate, 5-hydroperoxyeicosatetraenoic acid (5-HPETE).…”

Section: Introductionmentioning

confidence: 99%

Characterization of prostaglandin E2 generation through the cyclooxygenase (COX)-2 pathway in human neutrophils

St-Onge

Flamand

Biarc

et al. 2007

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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In the present study, we characterized the generation of prostaglandin (PG)E 2 in human neutrophils. We found that the Ca 2+ -dependent type IV cytosolic phospholipase A 2 (cPLA 2 ) was pivotally involved in the COX-2-mediated generation of PGE 2 in response to a calcium ionophore, as determined by the use of selected PLA 2 inhibitors. PGE 2 biosynthesis elicited by bacterialderived peptides or by phagocytic stimuli acting on cell surface receptors also showed to be dependent on cPLA 2 activity. We then assessed metabolism of unesterified arachidonic acid (AA), and observed that PGE 2 production becomes favored over that of LTB 4 with higher AA concentrations. Withdrawal of calcium prevented the generation of PGE 2 in response to a calcium ionophore but did not affect the up-regulation of COX-2 or its capacity to convert AA, thus limiting its implication at the level of cPLA 2 activation. Of the main eicosanoids produced by neutrophils, only LTB 4 was able to up-regulate COX-2 expression. Finally, the only PGE synthase isoform found in neutrophils is microsomal PGE synthase-1; it co-localized with COX-2 and its expression appeared mainly constitutive. These results highlight key differences in regulatory processes of the 5-LO and COX pathways, and enhance our knowledge at several levels in the PGE 2 biosynthesis in neutrophils.

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“…Most AA and DHA are incorporated in the sn-2 position of phospholipids, with AA and DHA released from phospholipids by selective phospholipases (PLA 2 ) upon activation [75][76]. Most of the released AA and DHA undergo reincorporation into available sn-2 positions of lysophospholipids via acyl-CoA synthetase and acyltransferase [36].…”

Section: Fabp7/fatty Acid Mechanisms Controlling Malignant Glioma Migmentioning

confidence: 99%

“…If these peroxidized fatty acids were to be retained in the membrane structure, this would lead to disruption of the membrane. PLA 2 s are therefore critical for the integrity of the membrane structure under normal physiological conditions [75]. Peroxidized fatty acids are then reduced by reaction with glutathione peroxidase and membrane repair is completed by reacylation with long-chain fatty acyl-CoA.…”

Section: Fabp7/fatty Acid Mechanisms Controlling Malignant Glioma Migmentioning

confidence: 99%

“…Different PLA 2 isoforms show different substrate selectivity with cPLA 2 and iPLA 2 being selective for AA and DHA-containing phospholipids, respectively. sPLA 2 has no apparent selectivity requirement in vitro [75,[78][79]. Furthermore, iPLA 2 appears to be involved in membrane phospholipid homeostasis and is up-regulated in response to increased phosphatidylcholine synthesis [80][81].…”

Section: Fabp7/fatty Acid Mechanisms Controlling Malignant Glioma Migmentioning

confidence: 99%

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Interaction of brain fatty acid-binding protein with the polyunsaturated fatty acid environment as a potential determinant of poor prognosis in malignant glioma

Elsherbiny

Emara

Godbout

2013

Progress in Lipid Research

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Malignant gliomas are the most common adult brain cancers. In spite of aggressive treatment, recurrence occurs in the great majority of patients and is invariably fatal. Polyunsaturated fatty acids are abundant in brain, particularly ω-6 arachidonic acid (AA) and ω-3 docosahexaenoic acid (DHA). Although the levels of ω-6 and ω-3 polyunsaturated fatty acids are tightly regulated in brain, the ω-6:ω-3 ratio is dramatically increased in malignant glioma, suggesting deregulation of fundamental lipid homeostasis in brain tumor tissue. The migratory properties of malignant glioma cells can be modified by altering the ratio of AA:DHA in growth medium, with increased migration observed in AA-rich medium. This fatty acid-dependent effect on cell migration is dependent on expression of the brain fatty acid binding protein (FABP7) previously shown to bind DHA and AA. Increased levels of enzymes involved in eicosanoid production in FABP7-positive malignant glioma cells suggest that FABP7 is an important modulator of AA metabolism. We provide evidence that increased production of eicosanoids in FABP7-positive malignant glioma growing in an AA-rich environment contributes to tumor infiltration in the brain. We discuss pathways and molecules that may underlie FABP7/AA-mediated promotion of cell migration and FABP7/DHA-mediated inhibition of cell migration in malignant glioma.

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Phospholipase A2 isoforms: a perspective

Cited by 169 publications

References 257 publications

TNF-α Inhibits Macrophage Clearance of Apoptotic Cells via Cytosolic Phospholipase A2 and Oxidant-Dependent Mechanisms

TNF-α Inhibits Macrophage Clearance of Apoptotic Cells via Cytosolic Phospholipase A2 and Oxidant-Dependent Mechanisms

Characterization of prostaglandin E2 generation through the cyclooxygenase (COX)-2 pathway in human neutrophils

Interaction of brain fatty acid-binding protein with the polyunsaturated fatty acid environment as a potential determinant of poor prognosis in malignant glioma

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