Involvement of Phosphatidate Phosphohydrolase in Arachidonic Acid Mobilization in Human Amnionic WISH Cells

Balboa, Marı́a A.; Balsinde, Jesús; Dennis, Edward A.

doi:10.1074/jbc.273.13.7684

Cited by 64 publications

(70 citation statements)

References 39 publications

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“…To obtain further evidence for the above observation, AA incorporation experiments were carried out in the presence of propranolol, a phosphatidate phosphatase-1 inhibitor that blunts fatty acid incorporation via de novo but not via direct deacylation/ reacylation reactions (38)(39)(40)(41)(42). A strong inhibition of AA incorporation into triacylglycerol was observed in stimulated monocytes treated with propranolol (Fig.…”

Section: Aa Incorporation Into Pls In Activated Cells Occurs Primarilmentioning

confidence: 82%

Signaling Role for Lysophosphatidylcholine Acyltransferase 3 in Receptor-Regulated Arachidonic Acid Reacylation Reactions in Human Monocytes

Pérez-Chacón

Astudillo²,

Ruipérez³

et al. 2009

The Journal of Immunology

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Cellular availability of free arachidonic acid (AA) is an important step in the production of pro- and anti-inflammatory eicosanoids. Control of free AA levels in cells is carried out by the action of phospholipase A2s and lysophospholipid acyltransferases, which are responsible for the reactions of deacylation and incorporation of AA from and into the sn-2 position of phospholipids, respectively. In this work, we have examined the pathways for AA incorporation into phospholipids in human monocytes stimulated by zymosan. Our data show that stimulated cells exhibit an enhanced incorporation of AA into phospholipids that is not secondary to an increased availability of lysophospholipid acceptors due to phospholipase A2 activation but rather reflects the receptor-regulated nature of the AA reacylation pathway. In vitro activity measurements indicate that the receptor-sensitive step of the AA reacylation pathway is the acyltransferase using lysophosphatidylcholine (lysoPC) as acceptor, and inhibition of the enzyme lysoPC acyltransferase 3 by specific small interfering RNA results in inhibition of the stimulated incorporation of AA into phospholipids. Collectively, these results define lysoPC acyltransferase 3 as a novel-signal–regulated enzyme that is centrally implicated in limiting free AA levels in activated cells.

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Section: Aa Incorporation Into Pls In Activated Cells Occurs Primarilmentioning

confidence: 82%

Signaling Role for Lysophosphatidylcholine Acyltransferase 3 in Receptor-Regulated Arachidonic Acid Reacylation Reactions in Human Monocytes

Pérez-Chacón

Astudillo²,

Ruipérez³

et al. 2009

The Journal of Immunology

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“…Thus, iPLA 2 ␤, and not iPLA 2 ␥, is the likely mediator of AA release in this system. (33,34) have suggested that cytosolic phosphatidate phosphohydrolase (PAP-1) in some cell types may be a target for BEL and that the resulting inhibition of PAP-1 would result in diminished levels of diacylglycerol produced from phosphatidic acid, thereby attenuating PKC activation precluding cPLA 2 ␣ activation and AA release. To address this possibility, we first examined the effects of rac-BEL on A-10 cell PAP activities in cytosol and membrane fractions (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, we have observed cell death employing 100 M BEL which is almost certainly independent of the effects of BEL on targeted processes. 4 Dennis and co-workers have contended that high concentrations of rac-BEL (Ϸ 25 M) effectively inhibit magnesium-dependent cytosolic phosphatidate phosphohydrolase (PAP-1) in mouse P388D 1 macrophages (33) and human amnionic WISH cells (34). The authors argue that inhibition of PAP-1 would be expected to cause a deficiency in DAG, thus blunting PKC activation and possibly activation of cPLA 2 ␣ by MAPK.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, it became necessary to develop pharmacologic approaches that could discriminate between iPLA 2 ␤ and iPLA 2 ␥ to facilitate identification of their biologic roles. In addition, it has been reported previously (33,34) that high concentrations of BEL (25 M) partially inhibit the magnesium-dependent cytosolic phosphatidate phosphohydrolase, PAP-1, which converts phosphatidic acid to diacylglycerol (DAG). In those investigations, it was proposed that PAP-1 inhibition by BEL would prevent activation of protein kinase C leading to attenuated AA release.…”

mentioning

confidence: 94%

“…In those investigations, it was proposed that PAP-1 inhibition by BEL would prevent activation of protein kinase C leading to attenuated AA release. However, "rescue" experiments in which PKC was exogenously activated by phorbol esters or diacylglycerol analogs after BEL treatment were not reported by the authors to address their hypothesis (33,34).…”

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confidence: 97%

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Identification of Calcium-independent Phospholipase A2 (iPLA2) β, and Not iPLA2γ, as the Mediator of Arginine Vasopressin-induced Arachidonic Acid Release in A-10 Smooth Muscle Cells

Jenkins

Han

Mancuso

et al. 2002

Journal of Biological Chemistry

166

187

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The agonist-stimulated release of arachidonic acid (AA) from cellular phospholipids in many cell types (e.g. myocytes, ␤-cells, and neurons) has been demonstrated to be primarily mediated by calcium-independent phospholipases A 2 (iPLA 2 s) that are inhibited by the mechanism-based inhibitor (E)-6-(bromomethylene)-3-(1-naphthalenyl)-2H-tetrahydropyran-2-one (BEL). Recently, the family of mammalian iPLA 2 s has been extended to include iPLA 2 ␥, which previously could not be pharmacologically distinguished from iPLA 2 ␤. To determine whether iPLA 2 ␤ or iPLA 2 ␥ (or both) were the enzymes responsible for arginine vasopressin (AVP)-induced AA release from A-10 cells, it became necessary to inhibit selectively iPLA 2 ␤ and iPLA 2 ␥ in intact cells. We hypothesized that the R-and S-enantiomers of BEL would possess different inhibitory potencies for iPLA 2 ␤ and iPLA 2 ␥. Accordingly, racemic BEL was separated into its enantiomeric constituents by chiral high pressure liquid chromatography. Remarkably, (S)-BEL was approximately an order of magnitude more selective for iPLA 2

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Novel Majeed Syndrome–Causing LPIN2 Mutations Link Bone Inflammation to Inflammatory M2 Macrophages and Accelerated Osteoclastogenesis

Bhuyan

Jesús

Mitchell

et al. 2021

Arthritis & Rheumatology

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Objective. To identify novel heterozygous LPIN2 mutations in a patient with Majeed syndrome and characterize the pathomechanisms that lead to the development of sterile osteomyelitis.Methods. Targeted genetic analysis and functional studies assessing monocyte responses, macrophage differentiation, and osteoclastogenesis were conducted to compare the pathogenesis of Majeed syndrome to interleukin-1 (IL-1)-mediated diseases including neonatal-onset multisystem inflammatory disease (NOMID) and deficiency of the IL-1 receptor antagonist (DIRA).Results. A 4-year-old girl of mixed ethnic background presented with sterile osteomyelitis and elevated acute-phase reactants. She had a 17.8-kb deletion on the maternal LPIN2 allele and a splice site mutation, p.R517H, that variably spliced out exons 10 and 11 on the paternal LPIN2 allele. The patient achieved long-lasting remission receiving IL-1 blockade with canakinumab. Compared to controls, monocytes and monocyte-derived M1-like macrophages from the patient with Majeed syndrome and those with NOMID or DIRA had elevated caspase 1 activity and IL-1β secretion. In contrast, lipopolysaccharide-stimulated, monocyte-derived, M2-like macrophages from the patient with Majeed syndrome released higher levels of osteoclastogenic mediators (IL-8, IL-6, tumor necrosis factor, CCL2, macrophage inflammatory protein 1α/β, CXCL8, and CXCL1) compared to NOMID patients and healthy controls. Accelerated osteoclastogenesis in the patient with Majeed syndrome was associated with higher NFATc1 levels, enhanced JNK/MAPK, and reduced Src kinase activation, and partially responded to JNK inhibition and IL-1 (but not IL-6) blockade.Conclusion. We report 2 novel compound heterozygous disease-causing mutations in LPIN2 in an American patient with Majeed syndrome. LPIN2 deficiency drives differentiation of proinflammatory M2-like macrophages and enhances intrinsic osteoclastogenesis. This provides a model for the pathogenesis of sterile osteomyelitis which differentiates Majeed syndrome from other IL-1-mediated autoinflammatory diseases.ClinicalTrials.gov identifier: NCT02974595.

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Involvement of Phosphatidate Phosphohydrolase in Arachidonic Acid Mobilization in Human Amnionic WISH Cells

Cited by 64 publications

References 39 publications

Signaling Role for Lysophosphatidylcholine Acyltransferase 3 in Receptor-Regulated Arachidonic Acid Reacylation Reactions in Human Monocytes

Signaling Role for Lysophosphatidylcholine Acyltransferase 3 in Receptor-Regulated Arachidonic Acid Reacylation Reactions in Human Monocytes

Identification of Calcium-independent Phospholipase A2 (iPLA2) β, and Not iPLA2γ, as the Mediator of Arginine Vasopressin-induced Arachidonic Acid Release in A-10 Smooth Muscle Cells

Novel Majeed Syndrome–Causing LPIN2 Mutations Link Bone Inflammation to Inflammatory M2 Macrophages and Accelerated Osteoclastogenesis

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