5‐lipoxygenase‐activating protein is an arachidonate binding protein

Mancini, Joseph A.; Abramovitz, Mark; Cox, Martha E.; Wong, Elizabeth; Charleson, S.; Perrier, Hélène; Wang, Zhaoyin; Prasit, Petpiboon; Vickers, Philip J.

doi:10.1016/0014-5793(93)80528-3

Cited by 202 publications

(132 citation statements)

References 20 publications

(6 reference statements)

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“…FLAP is an AA binding protein that stimulates the utilization of AA by 5-LO and also augments 5-LO membrane association. By affecting the ratio of 5-LO products (5-HETE/LTA 4 ), FLAP increases the efficiency of LTA 4 synthesis (23)(24)(25). Indeed, we could show that the FLAP inhibitor MK-886 was able to impair LXA 4 and RvD 1 biosynthesis in precursortreated PMNLs.…”

Section: Discussionmentioning

confidence: 78%

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Lipoxin and resolvin biosynthesis is dependent on 5‐lipoxygenase activating protein

et al. 2015

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Resolution of acute inflammation is an active process coordinated by proresolving lipid mediators (SPMs) such as lipoxins (LXs) and resolvins (Rvs), which are formed by the concerted action of 2 lipoxygenases (LOs). Because the exact molecular mechanisms of SPM biosynthesis are not completely understood, we aimed to investigate LX and D-type Rv formation in human leukocytes and HEK293T cells overexpressing leukotriene (LT) pathway enzymes. Activity assays in precursor (15-hydroxyeicosatetraenoic acids, 17-HDoHE)-treated granulocytes [polymorphonuclear leukocytes (PMNLs)] showed a strict dependence of LXA 4 /RvD 1 biosynthesis on cell integrity, and incubation with recombinant human 5-LO did not lead to LX or Rv formation. Pharmacologic inhibition of 5-LO activating protein (FLAP) by MK-886 inhibited LXA 4 /RvD 1 biosynthesis in precursor-treated PMNLs (drug concentration causing 50% inhibition ∼0.3/0.2 mM), as did knockdown of the enzyme in MM6 cells, and precursor-treated HEK293T overexpressing 5-LO produced high amounts of LXA 4 only in the presence of FLAP. In addition, inhibition of cytosolic phospholipase A 2a (cPLA 2a ) interfered with LXA 4 / RvD 1 formation from exogenous precursors in PMNLs. Furthermore, inhibition of the LT synthases LTA 4 hydrolase and LTC 4 synthase in PMNL/platelet coincubations augmented LXA 4 levels. These findings show that several enzymes known to be involved in the biosynthesis of proinflammatory LTs, such as FLAP and cPLA 2a , also contribute to LX and Rv formation.-

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Section: Discussionmentioning

confidence: 78%

“…In LT biosynthesis, FLAP is thought to transfer liberated AA to activated 5-LO (23)(24)(25). In addition, it also fosters the membrane association of 5-LO (26).…”

Section: Resultsmentioning

confidence: 99%

Lipoxin and resolvin biosynthesis is dependent on 5‐lipoxygenase activating protein

et al. 2015

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“…Conversion of AA to 5-HPETE followed a function of AA availability while the transformation of 5-HPETE to LTA 4 followed a bell-shaped curve, indicating that the second enzymatic reaction catalyzed by 5-LO, but not the first, is affected at higher AA concentrations. Although the explanation for this inhibition is not clear, high concentrations of AA were previously reported to bind to FLAP [46] and to inhibit LT biosynthesis [38]. Also, in a recent study where 5-lipoxygenase-activating protein (FLAP) was shown to be present in neutrophil membranes as monomers and homodimers, and where the functional importance of the dimer (over the monomer) in LT biosynthesis was highlighted [47], it was observed that high AA concentrations decreased FLAP dimer levels, supporting the possibility that high concentrations of AA could disrupt or destabilize the FLAP dimer, an effect which correlates with the suppression of 5-LO product biosynthesis by the fatty acid.…”

Section: Discussionmentioning

confidence: 96%

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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“…In the first steps of LT biosynthesis, AA liberated by the action of phospholipase A 2 (PLA 2 ), in particular cytosolic PLA 2 (cPLA 2 ), is transferred to 5-LO by 5-LOactivating protein (FLAP) (6,7). Upon activation, 5-LO translocates to the nuclear envelope, in which FLAP is localized (8,9).…”

mentioning

confidence: 99%

Prostaglandins Inhibit 5-Lipoxygenase-Activating Protein Expression and Leukotriene B4 Production from Dendritic Cells Via an IL-10-Dependent Mechanism

Harizi

Juzan

Moreau

et al. 2003

The Journal of Immunology

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PGs produced from arachidonic acid by the action of cyclooxygenase enzymes play a pivotal role in the regulation of both inflammatory and immune responses. Because leukotriene B4 (LTB4), a product of 5-lipoxygenase (5-LO) pathway, can exert numerous immunoregulatory and proinflammatory activities, we examined the effects of PGs on LTB4 release from dendritic cells (DC) and from peritoneal macrophages. In concentration-dependent manner, PGE1 and PGE2 inhibited the production of LTB4 from DC, but not from peritoneal macrophage, with an IC50 of 0.04 μM. The same effect was observed with MK-886, a 5-LO-activating protein (FLAP)-specific inhibitor. The decreased release of LTB4 was associated with an enhanced level of IL-10. Furthermore, the inhibition of LTB4 synthesis by PGs was significantly reversed by anti-IL-10, suggesting the involvement of an IL-10-dependent mechanism. Hence, we examined the effects of exogenous IL-10 on the 5-LO pathway. We demonstrate that IL-10 suppresses the production of LTB4 from DC by inhibiting FLAP protein expression without any effect on 5-LO and cytosolic phospholipase A2. Taken together, our results suggest links between DC cyclooxygenase and 5-LO pathways during the inflammatory response, and FLAP is a key target for the PG-induced IL-10-suppressive effects.

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5‐lipoxygenase‐activating protein is an arachidonate binding protein

Cited by 202 publications

References 20 publications

Lipoxin and resolvin biosynthesis is dependent on 5‐lipoxygenase activating protein

Lipoxin and resolvin biosynthesis is dependent on 5‐lipoxygenase activating protein

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

Prostaglandins Inhibit 5-Lipoxygenase-Activating Protein Expression and Leukotriene B4 Production from Dendritic Cells Via an IL-10-Dependent Mechanism

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