Analogs of leukotriene B4: Effects of modification of the hydroxyl groups on leukocyte aggregation and binding to leukocyte leukotriene B4 receptors

Leblanc, Yves; Fitzsimmons, Brian J.; Alexander, Peter; Evans, Jillian F.; Rokach, Joshua

doi:10.1016/0090-6980(87)90029-3

Cited by 23 publications

(19 citation statements)

References 19 publications

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“…The 20, 20, 20-trifluoro-LTB 4 analog also triggered the release of anti-HSV-1 compounds while all other analogs tested were unable to induce the release of virucidal molecules, when assayed at 100 nM. These data are in agreement with previous studies where 12-epi-LTB 4 and 20,20,20-trifluoro-LTB 4 were reported to show significant biological activities, although lower than those of LTB 4 (36,37), while several other analogs were found to Ն100-fold less active than LTB 4 (38).…”

Section: Supernatants From Ltb 4 -Activated Pmn Efficiently Neutralizsupporting

confidence: 83%

Leukotriene B4 Triggers the In Vitro and In Vivo Release of Potent Antimicrobial Agents

Flamand

Tremblay

Borgeat

2007

The Journal of Immunology

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Leukotriene B4 (LTB4) is a bioactive lipid derived from the metabolism of arachidonic acid. Mainly produced by polymorphonuclear leukocytes (PMN) and macrophages, LTB4 triggers several functional responses important in host defense, including the secretion of lysosomal enzymes, the activation of NADPH oxidase activity, NO formation, and phagocytosis. We report that LTB4, but not structural analogs thereof, stimulates primed human PMN to release molecules having potent antimicrobial activities. Exposure of bacteria (Escherichia coli and Staphylococcus aureus) or viruses (herpes simplex virus type 1 and HIV type 1) to supernatants of LTB4-activated PMN lead to ≥90% reduction in infectivity. ELISA and mass spectroscopy analysis of proteins released from LTB4-activated PMN have identified several antimicrobial proteins, including α-defensins, cathepsin G, elastase, lysozyme C, and LL-37, that are likely to participate in the killing of microorganisms. In addition to these in vitro observations, i.v. injections of LTB4 (50 μg/kg) to monkeys led to an increase in α-defensin plasmatic levels and enhanced ex vivo antimicrobial activities of plasma. These results demonstrate the ability of LTB4 to cause the release of potent antimicrobial agents from PMN in vitro as well as in vivo and add further support to the important role of LTB4 in host defense.

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Section: Supernatants From Ltb 4 -Activated Pmn Efficiently Neutralizsupporting

confidence: 83%

Leukotriene B4 Triggers the In Vitro and In Vivo Release of Potent Antimicrobial Agents

Flamand

Tremblay

Borgeat

2007

The Journal of Immunology

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“…The described activation of phospholipase A2 and the enhanced release of arachidonic acid from lymphocytes and macrophages by other plant lectins, namely concanavalin A and wheat germ agglutinin [20,21] BIOCHEMISTRYand MOLECULAR BIOLOGY INTERNATIONAL NDGA [2,22]. Leukotriene B4 and its analogues themselves are potent inducers of aggregation [23]. Therefore, the obtained results allow to propose that the galactoside-specific lectin VAA or a secondary cell contact-dependent mechanism promote the synthesis of leukotrienes in human neutrophils and rat thymocytes.…”

Section: Resultsmentioning

confidence: 96%

Metabolic inhibitors as tools to delineate participation of distinct intracellular pathways in enhancement of lactose‐induced dissociation of neutrophil and thymocyte aggregates formed by mediation of a plant lectin

et al. 1997

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Summary: Signaling processes in the course of the formation of the lectin-mediated aggregates may partake in conveying enhanced stability to the cell clusters. To prove the validity of this reasoning in a model, we have studied the impact of addition of three metabolic inhibitors (Nethylmaleimide, nordihydroguaiaretic acid, and trifluoperazine) on lactose-dependent dissociation of cell aggregates, formed in the presence of the galactoside-binding mistletoe lectin. Using both human neutrophils and rat thymocytes to avoid measurement of responses restricted to a single cell type, an enhanced dissociation of lectin-formed cell aggregates was observed, when lactose and an inhibitor were present. Among the tested inhibitors, nordihydroguaiaretic acid and Nethylmateimide were more potent enhancers of cell dissociation than trifluoperazine. These results suggest that biosignaling pathways connected with lipoxygenase activity as well as the level of intracellular sulfhydryl groups confer further stability to lectin-dependent cell aggregates. The systematic evaluation of inhibitors for defined activities is thus suggested as a tool to disclose the nature and the contribution of individual signaling mechanisms to post-binding effects following lectin-initiated cell contact formation.

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“…peripheral leukocytes, including neutrophils and eosinophils, as well as peritoneal macrophages (37,38). The chemical properties of LTB 4 that are crucial for agonistic action at the BLT 1 receptor include a ⌬ 6 -cis-⌬ 8 -trans-⌬ 10 -trans double bond geometry and an R-configuration of the hydroxyl group at C-12, as determined by structure-activity studies (21)(22)(23). Previous work on mutated enzymes and non-mammalian LTA4H have indicated that a precise alignment of LTA 4 in the active site is also very important for catalysis and formation of the proper chemistry in the product LTB 4 (18, 39 -41).…”

Section: Discussionmentioning

confidence: 99%

“…The epoxide hydrolase reaction of LTA4H is also unique in the sense that the stereoselective introduction of water to the carbon backbone of LTA 4 occurs several methylene units away from the epoxide moiety, presumably proceeding via a carbocation intermediate (19). Furthermore, Asp 375 was shown to assist in the introduction of the 12R hydroxyl group of LTB 4 (20), a key component for the biologic activity of LTB 4 (21)(22)(23).…”

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confidence: 99%

Leukotriene A4 Hydrolase

Rudberg

Tholander

Andberg

et al. 2004

Journal of Biological Chemistry

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Leukotriene (LT) A 4 hydrolase is a bifunctional zinc metalloenzyme, which converts LTA 4 into the neutrophil chemoattractant LTB 4 and also exhibits an anion-dependent aminopeptidase activity. In the x-ray crystal structure of LTA 4 The leukotrienes (LTs) 1 are a class of structurally related lipid mediators involved in the development and maintenance of inflammatory and allergic reactions (1, 2). In the biosynthesis of LTs, 5-lipoxygenase converts arachidonic acid into the unstable epoxide LTA 4 . This intermediate may in turn be conjugated with glutathione to form the spasmogenic LTC 4 , or hydrolyzed into the proinflammatory lipid mediator LTB 4 , in a reaction catalyzed by LTA 4 hydrolase (LTA4H). Leukotriene B 4 is a classical chemoattractant of human neutrophils and triggers adherence and aggregation of leukocytes to vascular endothelium at only nanomolar concentrations (3). In addition, LTB 4 modulates immune responses (4, 5) and recent studies show that this lipid mediator is involved in early effector CD4 ϩ and CD8ϩ T cell recruitment to sites of inflammation (6 -8). Moreover, LTB 4 participates in the host-defense against infections (9, 10) and is a key mediator of platelet activating factorinduced lethal shock (11-13). These effects are signaled via specific, G protein-coupled receptors for LTB 4 (BLT 1 and BLT 2 ) (14, 15). The relative contributions of these two receptors to signaling and bioactivity are presently not clear.LTA4H (EC 3.3.2.6) is a bifunctional zinc metalloenzyme, exhibiting an anion-dependant aminopeptidase activity in addition to its epoxide hydrolase activity, i.e.

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Analogs of leukotriene B4: Effects of modification of the hydroxyl groups on leukocyte aggregation and binding to leukocyte leukotriene B4 receptors

Cited by 23 publications

References 19 publications

Leukotriene B4 Triggers the In Vitro and In Vivo Release of Potent Antimicrobial Agents

Leukotriene B4 Triggers the In Vitro and In Vivo Release of Potent Antimicrobial Agents

Metabolic inhibitors as tools to delineate participation of distinct intracellular pathways in enhancement of lactose‐induced dissociation of neutrophil and thymocyte aggregates formed by mediation of a plant lectin

Leukotriene A4 Hydrolase

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