5-Oxo-Eicosatetraenoate, a Potent Human Neutrophil Stimulus

O’Flaherty, Joseph T.; Cordes, J.; Redman, J F; Thomas, Michael J.

doi:10.1006/bbrc.1993.1391

Cited by 48 publications

(48 citation statements)

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“…1B). PGD 2 stimulates calcium mobilization (20) and a variety of other responses (14) in eosinophils but not neutrophils, whereas 5-oxo-ETE activates both eosinophils and neutrophils (21)(22)(23). This is confirmed in the present study.…”

Section: D-pgj 2 Is a Potent And Selective Stimulator Of Calcium Mosupporting

confidence: 84%

15-Deoxy-Δ12,1412,14-prostaglandins D2 and J2 Are Potent Activators of Human Eosinophils

Monneret

Vasilescu

et al. 2002

The Journal of Immunology

110

106

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15-Deoxy-Δ12,14-PDJ2 (15d-PGJ2) is a degradation product of PGD2 that has been proposed as an anti-inflammatory compound because of its various inhibitory effects, some of which are mediated by peroxisome proliferator-activated receptor-γ. In contrast to its reported inhibitory effects on macrophages and other cells, we found that this compound is a potent activator of eosinophils, inducing calcium mobilization, actin polymerization, and CD11b expression. It is selective for eosinophils, having little or no effect on neutrophils or monocytes. 15d-PGJ2 has an EC50 of ∼10 nM, similar to that of its precursor, PGD2. The concentrations of 15d-PGJ2 required to activate eosinophils are thus much lower than those required for its anti-inflammatory effects (usually micromolar). 15-Deoxy-Δ12,14-prostaglandin D2 (15d-PGD2) is also a potent activator of eosinophils, with an EC50 about the same as that of PGD2, whereas Δ12-PGJ2 is slightly less potent. Eosinophils pretreated with PGD2 no longer respond to 15d-PGJ2, and vice versa, but in both cases the cells still respond to another eicosanoid proinflammatory mediator, 5-oxo-6,8,11,14-eicosatetraenoic acid. This indicates that the effects of 15d-PGJ2 are mediated by the DP2/chemoattractant receptor-homologous molecule expressed on Th2 cells that has recently been identified in eosinophils. 15d-PGJ2 is selective for the DP2 receptor, in that it has no effect on DP1 receptor-mediated adenylyl cyclase activity in platelets. We conclude that 15d-PGJ2 and 15d-PGD2 are selective DP2 receptor agonists that activate human eosinophils with potencies at least 100 times greater than those for the proposed anti-inflammatory effects of 15d-PGJ2 on other cells.

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Section: D-pgj 2 Is a Potent And Selective Stimulator Of Calcium Mosupporting

confidence: 84%

15-Deoxy-Δ12,1412,14-prostaglandins D2 and J2 Are Potent Activators of Human Eosinophils

Monneret

Vasilescu

et al. 2002

The Journal of Immunology

110

106

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“…Our results thus support the previous conclusion that the PMN recognition systems for 5-HETE and LTB 4 are distinctive. We presume, as indicated in earlier work (28,52) that 5-HETE and 5-oxoETE operate through an identical cell-activating mechanism. Maximal increase in PLA 2 activity was seen with 1 nM LTB 4 , while 500 nM 5-HETE and between 50 and 500 nM 5-oxoETE were required to achieve the same level of response.…”

Section: Discussionsupporting

confidence: 68%

“…Maximal increase in PLA 2 activity was seen with 1 nM LTB 4 , while 500 nM 5-HETE and between 50 and 500 nM 5-oxoETE were required to achieve the same level of response. These differences in concentration required to activate the 85-kDa PLA 2 correlate well with their potencies in stimulating PMN function (28,51,52).…”

Section: Discussionmentioning

confidence: 98%

“…Zileuton (Abbott A 64077; N-hydroxy-N- (1-benzo[b]thien-2-ylethyl)urea) was a gift from SmithKline-Beecham Pharmaceuticals (King of Prussia, PA). LTB 4 , 5-HETE, 5-oxoETE, 15-oxoETE, and (5R,12R)-6,8,10,14-(Z,Z,Z,E)-eicosatetraenoic acid (compound I) were synthesized as described previously (27,28). Prostaglandin E 2 , prostaglandin D 2 , and prostaglandin I 2 were from Cayman Chemical Co. (Ann Arbor, MI).…”

Section: Materials-1-stearoyl-2-[1-mentioning

confidence: 99%

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5-Lipoxygenase Products Modulate the Activity of the 85-kDa Phospholipase A2 in Human Neutrophils

Wijkander

O’Flaherty

Nixon

et al. 1995

Journal of Biological Chemistry

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14C]arachidonoylphosphatidylcholine as substrate. A similar increase in cytosolic PLA 2 activity was induced by stimulation of neutrophils with leukotriene B 4 (LTB 4 ), 5-oxoeicosatetraenoic acid, or 5-hydroxyeicosatetraenoic acid (5-HETE). LTB 4 was the most potent of the agonists, showing maximal effect at 1 nM. Inhibition of 5-lipoxygenase with either eicosatetraynoic acid or zileuton prevented the AA-induced increase in PLA 2 activity but had no effect on the response induced by LTB 4 . Furthermore, pretreatment of neutrophils with a LTB 4 -receptor antagonist, LY 255283, blocked the AAand LTB 4 -induced activation of PLA 2 but did not influence the action of 5-HETE. Treatment of neutrophils with pancreatic PLA 2 also induced an increase in the activity of the cytosolic PLA 2 ; this response was inhibited by both eicosatetraynoic acid or LY 255283.The increases in PLA 2 activity in response to stimulation correlated with a shift in electrophoretic mobility of the 85-kDa PLA 2 , as determined by Western blot analysis, suggesting that phosphorylation of the 85-kDa PLA 2 likely underlies its increase in catalytic activity. Although stimulation of neutrophils with individual lipoxygenase metabolites did not induce significant mobilization of endogenous AA, they greatly enhanced the N-formylmethionyl-leucyl-phenylalanine-induced mobilization of AA as determined by mass spectrometry analysis. Our findings support a positive-feedback model in which stimulus-induced release of AA or exocytosis of secretory PLA 2 modulate the activity of the cytosolic 85-kDa PLA 2 by initiating the formation of LTB 4 . The nascent LTB 4 is then released to act on the LTB 4 receptor and thereby promote further activation of the 85-kDa PLA 2 . Since 5-HETE and LTB 4 are known to prime the synthesis of platelet-activating factor, the findings suggest that 85-kDa PLA 2 plays a role in platelet-activating factor synthesis.Arachidonic acid (AA) 1 is the precursor for prostaglandins and leukotrienes (collectively named eicosanoids), which together with platelet-activating factor (PAF) are important lipid mediators involved in allergic and inflammatory reactions. The initial step in the production of eicosanoids is hydrolysis of sn-2-arachidonate from membrane phospholipids generating free AA; phospholipase A 2 s (PLA 2 ) with different characteristics have been implicated in this hydrolysis (1-3). The 14-kDa PLA 2 s (type I and II) are secretory enzymes, and although they show no apparent preference for hydrolysis of AA-containing phospholipids (4, 5), they have been suggested to participate in the generation of eicosanoids after first being secreted by mobilizing AA from phospholipids on the outer leaflet of the plasma membrane (6 -12). The 85-kDa PLA 2 (13, 14) is an intracellular enzyme with clear preference for AA-containing phospholipids (5, 15, 16). Furthermore, the 85-kDa PLA 2 translocates to membranes in response to submicromolar concentrations of Ca 2ϩ (13,17,18) and is also regulated by phosphorylation, which results in an inc...

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“…This eicosanoid elicits a different set of important biological activities as a potent agonist increasing cytosolic calcium levels, chemotaxis, and degranulation by a mechanism independent of the LTB 4 receptor in the human neutrophil (11,12). Low concentrations have been shown to increase the surface expression of the ␤ 2 integrin CD11b, actin polymerization and adherence (13).…”

mentioning

confidence: 99%

Biosynthesis of 5-Oxo-6,8,11,14-eicosatetraenoic Acid from 5-Hydroperoxyeicosatetraenoic Acid in the Murine Macrophage

Zarini

Murphy

2003

Journal of Biological Chemistry

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5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a metabolite of arachidonic acid shown to possess important biological activities within different cell types. In the neutrophil, a specific NADP ؉ -dependent dehydrogenase utilizes 5-lipoxygenase-derived 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5(S)-HETE) as the required substrate. In the present study, 5-hydroperoxy-6,8,11,14-eicosatetraenoic acid (5-HpETE), rather than 5-HETE, was found to be the biosynthetic precursor of 5-oxo-ETE in the murine macrophage. The macrophage was not able to convert 5-HETE into 5-oxo-ETE even when preincubated with phorbol ester or with other lipid hydroperoxides. The factor responsible for the conversion of 5-HpETE into 5-oxo-ETE was found predominantly in the cytosolic fraction of the macrophage, with an approximate molecular weight of 50,000 -60,000, as assessed by size exclusion chromatography. Formation of 5-oxo-ETE was rapid and the catalytic protein was found to have an apparent K m of 5.3 M for the eicosanoid. Furthermore, the protein could efficiently utilize 5(R,S)-HpETE as substrate and was heat and protease labile. This novel pathway of 5-oxo-ETE biosynthesis in the murine macrophage was consistent with reduction of a 5-hydroperoxy group to an intermediate alkoxy radical that could be subsequently oxidized to the 5-oxo product. Such a mechanism would enable racemic 5-HpETE, derived from free radical oxidation of arachidonic acid, to be efficiently converted into this potent chemotactic eicosanoid.

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5-Oxo-Eicosatetraenoate, a Potent Human Neutrophil Stimulus

Cited by 48 publications

References 0 publications

15-Deoxy-Δ12,1412,14-prostaglandins D2 and J2 Are Potent Activators of Human Eosinophils

15-Deoxy-Δ12,1412,14-prostaglandins D2 and J2 Are Potent Activators of Human Eosinophils

5-Lipoxygenase Products Modulate the Activity of the 85-kDa Phospholipase A2 in Human Neutrophils

Biosynthesis of 5-Oxo-6,8,11,14-eicosatetraenoic Acid from 5-Hydroperoxyeicosatetraenoic Acid in the Murine Macrophage

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