Mechanisms of the priming effect of lipopolysaccharides on the biosynthesis of leukotriene B<sub>4</sub>in chemotactic peptide‐stimulated human neutrophils

Surette, Marc E.; Dallaire, Nancy; Jean, Nathalie; Picard, Serge; Borgeat, Pierre

doi:10.1096/fasebj.12.14.1521

Cited by 63 publications

(56 citation statements)

References 57 publications

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“…Second, exposing neutrophils to fMLP results in a decrease in the electrophoretic mobility of cPLA 2 , a finding consistent with cPLA 2 phosphorylation, and stimulates the translocation of cPLA 2 from cytosolic to microsomal and nuclear compartments (44,45). Third, co-incubating neutrophils with the cPLA 2 inhibitor methylarachidonyl fluorophosphonate (MAFP) decreases fMLP-stimulated arachidonic acid mass release (44,45). Fourth, peritoneal macrophages from mice subjected to targeted disruption of the cPLA 2 gene (cPLA 2 Ϫ/Ϫ ) produce less PGE 2 , LTB 4 , and platelet-activating factor following exposure to inflammatory stimuli than macrophages from wild type mice (cPLA 2 ϩ/ϩ ) (46,47).…”

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confidence: 61%

“…First, cPLA 2 selectively hydrolyzes phospholipids with arachidonic acid in the sn-2 position (43). Second, exposing neutrophils to fMLP results in a decrease in the electrophoretic mobility of cPLA 2 , a finding consistent with cPLA 2 phosphorylation, and stimulates the translocation of cPLA 2 from cytosolic to microsomal and nuclear compartments (44,45). Third, co-incubating neutrophils with the cPLA 2 inhibitor methylarachidonyl fluorophosphonate (MAFP) decreases fMLP-stimulated arachidonic acid mass release (44,45).…”

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confidence: 67%

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Groups IV, V, and X Phospholipases A2s in Human Neutrophils

Dégousée¹,

Ghomashchi²,

Stefanski³

et al. 2002

Journal of Biological Chemistry

165

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The bacterial tripeptide formyl-Met-Leu-Phe (fMLP) induces the secretion of enzyme(s) with phospholipase A 2 (PLA 2 ) activity from human neutrophils. We show that circulating human neutrophils express groups V and X sPLA 2 (GV and GX sPLA 2 ) mRNA and contain GV and GX sPLA 2 proteins, whereas GIB, GIIA, GIID, GIIE, GIIF, GIII, and GXII sPLA 2 s are undetectable. GV sPLA 2 is a component of both azurophilic and specific granules, whereas GX sPLA 2 is confined to azurophilic granules. Exposure to fMLP or opsonized zymosan results in the release of GV but not GX sPLA 2 and most, if not all, of the PLA 2 activity in the extracellular fluid of fMLPstimulated neutrophils is due to GV sPLA 2 . GV sPLA 2 does not contribute to fMLP-stimulated leukotriene B 4 production but may support the anti-bacterial properties of the neutrophil, because 10 -100 ng per ml concentrations of this enzyme lead to Gram-negative bacterial membrane phospholipid hydrolysis in the presence of human serum. By use of a recently described and specific inhibitor of cytosolic PLA 2 -␣ (group IV PLA 2 ␣), we show that this enzyme produces virtually all of the arachidonic acid used for the biosynthesis of leukotriene B 4 in fMLP-and opsonized zymosan-stimulated neutrophils, the major eicosanoid produced by these pro-inflammatory cells.

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confidence: 61%

mentioning

confidence: 67%

Groups IV, V, and X Phospholipases A2s in Human Neutrophils

Dégousée¹,

Ghomashchi²,

Stefanski³

et al. 2002

Journal of Biological Chemistry

165

View full text Add to dashboard Cite

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“…LPS was also reported to increase LTB 4 production in both cell types (46,47). Therefore, neutrophils and macrophages may be other sources of LTB 4 in the bone marrow of mice suffering from bone resorption diseases.…”

Section: Discussionmentioning

confidence: 97%

A distinctive role of the leukotriene B ₄ receptor BLT1 in osteoclastic activity during bone loss

Hikiji

Ishii

Yokomizo

et al. 2009

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

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Although leukotriene B4 (LTB4) is produced in various inflammatory diseases, its functions in bone metabolism remain unknown. Using mice deficient in the high-affinity LTB4 receptor BLT1, we evaluated the roles of BLT1 in the development of two bone resorption models, namely bone loss induced by ovariectomy and lipopolysaccharide. Through observations of bone mineral contents and bone morphometric parameters, we found that bone resorption in both models was significantly attenuated in BLT1-deficient mice. Furthermore, osteoclasts from BLT1-deficient mice showed reduced calcium resorption activities compared with wild-type osteoclasts. Osteoclasts expressed BLT1, but not the low-affinity LTB4 receptor BLT2, and produced LTB4. LTB4 changed the cell morphology of osteoclasts through the BLT1-Gi protein-Rac1 signaling pathway. Given the causal relationship between osteoclast morphology and osteoclastic activity, these findings suggest that autocrine/paracrine LTB4 increases the osteoclastic activity through the BLT1-Gi protein-Rac1 signaling pathway. Inhibition of BLT1 functions may represent a strategy for preventing bone resorption diseases.bone remodeling ͉ G protein-coupled receptor ͉ knockout mice ͉ lipid mediator ͉ osteoporosis ͉ L eukotriene B 4 (LTB 4 ), a metabolite of arachidonic acid, is a potent lipid mediator with various biological activities toward neutrophils and differentiated T cells, including chemotaxis, degranulation, and production of superoxide anions (1, 2). These actions of LTB 4 are mediated by specific cell surface receptors (BLTs). We previously cloned two distinct BLTs, BLT1 and BLT2 (3,4). BLT1 is a high-affinity receptor that mediates the inhibition of adenylate cyclase and calcium entry by coupling with the Gi-and Gq-classes of G proteins (5). BLT2 transduces comparable intracellular signals but has a lower affinity to LTB 4 (5). Although several hydroxyeicosatetraenoic acids were found to activate BLT2 (6), we recently identified 12(S)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid (12-HHT) as a very potent endogenous ligand for BLT2 (7). LTB 4 is produced in inf lammatory diseases such as psoriasis (8), bronchial asthma (9), ulcerative colitis (10), postischemic tissue injuries (11), and rheumatoid arthritis (12-15).Bone remodeling consists of old bone resorption by osteoclasts and new bone deposition by osteoblasts. Osteoclasts and osteoblasts participate in bone remodeling under the control of many hormones, cytokines (16,17), and autacoids, including lipid mediators (18). The effects of LTB 4 on bone resorption were investigated using organ cultures of mouse calvariae (19,20). LTB 4 enhanced calcium efflux from the mouse calvariae, suggesting that LTB 4 stimulates bone resorption (19). LTB 4 increased the formation of resorption pits by osteoclasts in rat bone tissues (20), suggesting that LTB 4 modulates bone resorption by increasing the number and/or activity of osteoclasts. However, few reports have provided definitive biochemical information about the mRNA/protein expression and ...

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“…2) confirms the in vivo relevance of our observations. PMN and eosinophils employ a combination of signaling by cytokine or toll-like receptors and G protein-coupled receptors to initiate LT synthesis (13)(14)(15). The identification of the same FLAP-containing protein species in both synovial PMN and in IgE-stimulated RBL-2H3 cells support a ubiquitous role for these structures in LT synthesis in IgE dependent and independent systems.…”

Section: Discussionmentioning

confidence: 99%

“…For example, in mast cells, the engagement of Fc R1 by IgE/antigen triggers LT synthesis, whereas in eosinophils and polymorphonuclear leukocytes (PMN), a combination of cytokines, G protein-coupled receptor ligands, or bacterial lipopolysaccaharide perform this function (13)(14)(15)). An emerging theme in cell biology and immunology is that assembly of multiprotein complexes transduces apparently disparate signals into a common read-out.…”

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confidence: 99%

The nuclear membrane organization of leukotriene synthesis

Mandal

Jones

Bair

et al. 2008

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

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Leukotrienes (LTs) are signaling molecules derived from arachidonic acid that initiate and amplify innate and adaptive immunity. In turn, how their synthesis is organized on the nuclear envelope of myeloid cells in response to extracellular signals is not understood. We define the supramolecular architecture of LT synthesis by identifying the activation-dependent assembly of novel multiprotein complexes on the outer and inner nuclear membranes of mast cells. These complexes are centered on the integral membrane protein 5-Lipoxygenase-Activating Protein, which we identify as a scaffold protein for 5-Lipoxygenase, the initial enzyme of LT synthesis. We also identify these complexes in mouse neutrophils isolated from inflamed joints. Our studies reveal the macromolecular organization of LT synthesis.inflammation ͉ multiprotein complex ͉ 5-lipoxygenase ͉ 5-lipoxygenase-activating protein L eukotrienes (LTs) are lipid signaling molecules derived from arachidonic acid (AA) that initiate and amplify innate and adaptive immune responses by regulating the recruitment and activation of leukocytes in inflamed tissues (1-3). Cells employ multiple mechanisms to prevent the inappropriate onset of pro-inflammatory signaling while requiring tightly coupled processes to trigger the generation of pro-inflammatory signaling molecules. The interplay of these processes is epitomized by the synthesis of LTB 4 and LTC 4 . In unstimulated myeloid cells, including mast cells, LT formation is held in abeyance by the cytosolic compartmentalization of cytosolic phospholipase A 2 (cPLA 2 ) (4, 5) and the cytosolic/nucleoplasmic localization of 5-lipoxygenase (5-LO) (6). LT formation is initiated by translocation of cPLA 2 to the Golgi and ER/nuclear envelope to release AA (4, 5). In parallel, 5-LO targets to the inner and outer nuclear membranes to initiate LT synthesis by converting AA to 5-HPETE and LTA 4 , a process that requires the integral nuclear envelope protein 5-lipoxygenase-activating protein (FLAP) (7-9). Although we have shown that LTC 4 synthase and FLAP constitutively interact on the nuclear envelope (10), how or whether 5-LO interacts with these proteins on the nuclear envelope in response to cell signaling is unknown.Understanding how cells couple the reorganization of the LT biosynthetic enzymes to efficient AA utilization is central to understanding the signal transduction pathways that control the synthesis of bioactive lipids derived from AA. Scaffold/docking proteins can localize components of biochemical reactions at membrane interfaces; examples include protein kinase A anchoring proteins (11) and the integral membrane proteins caveolins 1-3 (12). The dependence of cellular LT synthesis on FLAP (7, 8) and its membrane localization (9) make it a conceptually appealing candidate for a 5-LO scaffold. However, no interaction of 5-LO with any membrane protein has been detected.A closely related question is: how do different combinations of extracellular signals lead to LT generation? For example, in mast cells, the engage...

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Mechanisms of the priming effect of lipopolysaccharides on the biosynthesis of leukotriene B₄in chemotactic peptide‐stimulated human neutrophils

Cited by 63 publications

References 57 publications

Groups IV, V, and X Phospholipases A2s in Human Neutrophils

Groups IV, V, and X Phospholipases A2s in Human Neutrophils

A distinctive role of the leukotriene B ₄ receptor BLT1 in osteoclastic activity during bone loss

The nuclear membrane organization of leukotriene synthesis

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Mechanisms of the priming effect of lipopolysaccharides on the biosynthesis of leukotriene B4in chemotactic peptide‐stimulated human neutrophils

Cited by 63 publications

References 57 publications

Groups IV, V, and X Phospholipases A2s in Human Neutrophils

Groups IV, V, and X Phospholipases A2s in Human Neutrophils

A distinctive role of the leukotriene B 4 receptor BLT1 in osteoclastic activity during bone loss

The nuclear membrane organization of leukotriene synthesis

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Product

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Mechanisms of the priming effect of lipopolysaccharides on the biosynthesis of leukotriene B₄in chemotactic peptide‐stimulated human neutrophils

A distinctive role of the leukotriene B ₄ receptor BLT1 in osteoclastic activity during bone loss