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Review
. 2013 Oct;52(4):651-65.
doi: 10.1016/j.plipres.2013.09.001. Epub 2013 Sep 19.

The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor

Affiliations
Review

The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor

William S Powell et al. Prog Lipid Res. 2013 Oct.

Abstract

5-Oxo-ETE (5-oxo-6,8,11,14-eicosatetraenoic acid) is formed from the 5-lipoxygenase product 5-HETE (5S-hydroxy-6,8,11,14-eicosatetraenoic acid) by 5-hydroxyeicosanoid dehydrogenase (5-HEDH). The cofactor NADP(+) is a limiting factor in the synthesis of 5-oxo-ETE because of its low concentrations in unperturbed cells. Activation of the respiratory burst in phagocytic cells, oxidative stress, and cell death all dramatically elevate both intracellular NADP(+) levels and 5-oxo-ETE synthesis. 5-HEDH is widely expressed in inflammatory, structural, and tumor cells. Cells devoid of 5-lipoxygenase can synthesize 5-oxo-ETE by transcellular biosynthesis using inflammatory cell-derived 5-HETE. 5-Oxo-ETE is a chemoattractant for neutrophils, monocytes, and basophils and promotes the proliferation of tumor cells. However, its primary target appears to be the eosinophil, for which it is a highly potent chemoattractant. The actions of 5-oxo-ETE are mediated by the highly selective OXE receptor, which signals by activating various second messenger pathways through the release of the βγ-dimer from Gi/o proteins to which it is coupled. Because of its potent effects on eosinophils, 5-oxo-ETE may be an important mediator in asthma, and, because of its proliferative effects, may also contribute to tumor progression. Selective OXE receptor antagonists, which are currently under development, could be useful therapeutic agents in asthma and other allergic diseases.

Keywords: 12-HHT; 12-hydroxy-5Z,8E,10E-heptadecatrienoic acid; 4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid; 5,12-diHETE; 5,15-diHETE; 5-HEDH; 5-HEPE; 5-HETE; 5-HETrE; 5-HODE; 5-HpETE; 5-LO; 5-Lipoxygenase; 5-Oxo-ETE; 5-hydroxyeicosanoid dehydrogenase; 5-lipoxygenase; 5-oxo-12-HETE; 5-oxo-12S-hydroxy-6E,8Z,10E,14Z-eicosatetraenoic acid; 5-oxo-15-HETE; 5-oxo-15S-hydroxy-6E,8Z,11Z,13E-eicosatetraenoic acid; 5-oxo-20-HETE; 5-oxo-20-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid; 5-oxo-6E,8Z,11Z,14Z,17Z-eicosapentaenoic acid; 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid; 5-oxo-6E,8Z,11Z-eicosatrienoic acid; 5-oxo-6E,8Z-octadecadienoic acid; 5-oxo-7-glutathionyl factor-8,11,14-eicosatrienoic acid; 5-oxo-EPE; 5-oxo-ETE; 5-oxo-ETrE; 5-oxo-ODE; 5S,12S-dihydroxy-6E,8Z,10E,14Z-eicosatetraenoic acid; 5S,15S-dihydroxy-6E,8Z,11Z,13E-eicosatetraenoic acid; 5S-hydroperoxy-6E,8Z,11Z,14Z-eicosatetraenoic acid; 5S-hydroxy-6E,8Z,11Z,14Z,17Z-eicosapentaenoic acid; 5S-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid; 5S-hydroxy-6E,8Z,11Z-eicosatrienoic acid; 5S-hydroxy-6E,8Z-octadecadienoic acid; 5Z,8Z,11Z,14Z,17Z-eicosapentaenoic acid; 5Z,8Z,11Z-eicosatrienoic acid; 5Z,8Z-octadecadienoic acid; Asthma; Chemoattractants; DHA; ECL; EPA; Eosinophils; FOG(7); G protein-coupled receptor; GPCR; Inflammation; LT; LXA(4); Mead acid; PAF; PI3K; PLC; PMA; PUFA; Sebaleic acid; StAR; eosinophil chemotactic lipid; leukotriene; lipoxin A(4); phorbol myristate acetate; phosphoinositide-3 kinase; phospholipase C; platelet-activating; polyunsaturated fatty acid; steroidogenic acute regulatory protein; uPAR; urokinase-type plasminogen activator receptor.

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Figures

Figure 1
Figure 1
Biosynthesis of 5-LO products from AA.
Figure 2
Figure 2. Regulation of intracellular NADP+ levels and 5-oxo-ETE synthesis
NADP+ is generated by the glutathione redox pathway in which GSH peroxidase (GPx) reduces H2O2 and oxidizes GSH to GSSG, which is reduced back to GSH by glutathione reductase (GRed) accompanied by the generation of NADP+. NADPH oxidase (NOX) also produces NADP+ when it reduces oxygen to superoxide. 5-Oxo-ETE synthesis is promoted by elevated levels of NADP+, which is also reduced back to NADPH by the pentose phosphate pathway, initiated by the action of glucose-6-phosphate dehydrogenase (G6Pdh) on glucose-6-phosphate (G6P). Both 5-oxo-ETE and 5-HETE are metabolized by ω-oxidation in the presence of NADPH.
Figure 3
Figure 3. Biosynthesis and metabolism of 5-oxo-ETE in different cell types
Neutrophils and eosinophils can synthesize and metabolize 5-oxo-ETE from endogenous AA, whereas PLC3 prostate cancer cells can synthesize 5-oxo-ETE from inflammatory cell-derived 5-HETE by transcellular biosynthesis. Platelets can also form 5-oxo-ETE in this way, but convert it to 12-hydroxy metabolites by the action of 12-LO. LTC4 synthase converts 5-oxo-ETE to FOG7 (broken line) although this has not yet been demonstrated to occur specifically in eosinophils.
Figure 4
Figure 4. Dendrogram showing the relationship of the OXE receptor to other eicosanoid receptors (large circles) as well as to other closely related receptors (small circles)
This was constructed using the facilities at www.phylogeny.fr [156].
Figure 5
Figure 5. Homology between the human OXE receptor protein sequence and those of OXE receptors from other selected species
Identical and different amino acids are shown in red and cyan, respectively, whereas missing and additional amino acids are shown in black and blue, respectively. Sequence comparisons were made using BLAST on the NCBI website.
Figure 6
Figure 6
Features of 5-oxo-ETE that are important for activation of the OXE receptor, based on structure-activity relationships in human neutrophils and eosinophils.
Figure 7
Figure 7. Intracellular signaling in response to activation of the OXE receptor
The inhibitory effect of 5-oxo-ETE on adenylyl cyclase (AC) is mediated by the αi G protein subunit, whereas all other effects are mediated by the βγ dimer.
Figure 8
Figure 8. 5-Oxo-ETE antagonists
Structures of 5-oxo-ETE, 5-oxo-12-HETE, the structure-based antagonist VG-346, and the biased antagonist Gue1654. The concentration-response curve for inhibition of 5-oxo-ETE-induced calcium mobilization in neutrophils by VG-346 is shown on the right.

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