5-Oxo-eicosanoids Are Potent Eosinophil Chemotactic Factors.

Schwenk, Uwe; Schröder, Jens‐Michael

doi:10.1074/jbc.270.25.15029

Cited by 85 publications

(40 citation statements)

References 28 publications

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“…Another 15-LO-1-derived metabolite, 5-oxo-15-hydroxy-6,8,11,13-eicosatetraenoic acid, produced by eosinophils, has been reported to be a potent chemotactic agent for human eosinophils (21). However, there are also indications that 15-LO-derived metabolites could play an antiinflammatory role because 15-LO-1 can be involved in the formation of lipoxins (22).…”

mentioning

confidence: 97%

Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells

Feltenmark¹,

Gautam²,

Brunnström³

et al. 2008

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

148

143

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Human eosinophils contain abundant amounts of 15-lipoxygenase (LO)-1. The biological role of 15-LO-1 in humans, however, is unclear. Incubation of eosinophils with arachidonic acid led to formation of a product with a UV absorbance maximum at 282 nm and shorter retention time than leukotriene (LT)C4 in reverse-phase HPLC. Analysis with positive-ion electrospray tandem MS identified this eosinophil metabolite as 14,15-LTC4. This metabolite could be metabolized to 14,15-LTD4 and 14,15-LTE4 in eosinophils. Because eosinophils are such an abundant source of these metabolites and to avoid confusion with 5-LO-derived LTs, we suggest the names eoxin (EX)C4, -D4, and -E4 instead of 14,15-LTC4, -D4, and -E4, respectively. Cord blood-derived mast cells and surgically removed nasal polyps from allergic subjects also produced EXC4. Incubation of eosinophils with arachidonic acid favored the production of EXC4, whereas challenge with calcium ionophore led to exclusive formation of LTC4. Eosinophils produced EXC4 after challenge with the proinflammatory agents LTC4, prostaglandin D2, and IL-5, demonstrating that EXC4 can be synthesized from the endogenous pool of arachidonic acid. EXs induced increased permeability of endothelial cell monolayer in vitro, indicating that EXs can modulate and enhance vascular permeability, a hallmark of inflammation. In this model system, EXs were 100 times more potent than histamine and almost as potent as LTC4 and LTD4. Taken together, this article describes the formation of proinflammatory EXs, in particular in human eosinophils but also in human mast cells and nasal polyps.

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mentioning

confidence: 97%

Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells

Feltenmark¹,

Gautam²,

Brunnström³

et al. 2008

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

148

143

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“…The boldface letters represent amino acids conserved in all of the prostanoid receptors aligned in Fig 6. The conserved amino acids in the prostanoid receptor are also found in TG1019: 103 5-oxo-ETE exhibited the most potent agonistic activity against TG1019. This eicosanoid is known as a potent chemotactic factor of eosinophils and neutrophils (37)(38)(39)(40). O'Flaherty et al (41,42), and O'Flaherty and Rossi (43) had revealed that the chemotactic activity would be mediated through a pertussis toxin-sensitive GPCR.…”

Section: Fig 5 Effect Of 5-oxo-ete On Forskolin-stimulated Camp Promentioning

confidence: 99%

Identification of a Novel Human Eicosanoid Receptor Coupled to Gi/o

Hosoi¹,

Koguchi²,

Sugikawa

et al. 2002

Journal of Biological Chemistry

147

137

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We have conducted an in silico data base search for and cloned a novel G-protein-coupled receptor (GPCR) named TG1019. Dot and Northern blotting analyses showed that transcripts of the novel GPCR were expressed in various tissues except brain, and the expression was more intense in liver, kidney, peripheral leukocyte, lung, and spleen than in other tissues. By GTP␥S binding assay using the TG1019-G␣ i1 -protein fusion expressed in insect cells, eicosanoids, and polyunsaturated fatty acids such as 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-oxo-ETE), 5(S)-hydroperoxy-6E,8Z, 11Z,14Z-eicosatetraenoic acid, and arachidonic acid were identified to exhibit agonistic activities against TG1019. 5-oxo-ETE was the most potent to enhance the specific binding by 6-fold at a maximum effect dose of submicromolar to micromolar order with an ED 50 value of 5.7 nM. Conversely, polyunsaturated fatty acids such as docosahexaenoic acid and eicosapentaenoic acid showed antagonistic activities against TG1019. In Chinese hamster ovary cells transiently expressing TG1019, the forskolin-stimulated production of cAMP was inhibited up to ϳ70% by 5-oxo-ETE, with an IC 50 value of 33 nM. This inhibition was sensitive to pretreatment of the cells with pertussis toxin.

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“…S2D). Six carbon-carbon double bonds hydrogenated 14S,21R-diHDHA (H 12 -14S,21R-diHDHA) was generated by bubbling hydrogen gas through a methanol solution of 14S,21R-diHDHA, in which Adam's catalyst PtO 2 (ϳ1 mg) was suspended (20 min, room temperature) (41)(42)(43).…”

Section: Sample Preparation and Lc-uv-ms/ms Analysis Of Lipid Mediatomentioning

confidence: 99%

14S,21R-Dihydroxydocosahexaenoic Acid Remedies Impaired Healing and Mesenchymal Stem Cell Functions in Diabetic Wounds

Tian

Lü

Shah

et al. 2011

Journal of Biological Chemistry

104

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Treatment of diabetes-impaired wound healing remains a major unresolved medical challenge. Here, we identified suppressed formation of a novel reparative lipid mediator 14S,21R-dihydroxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid (14S,21R-diHDHA) in cutaneous wounds of diabetic db/db mice. These results indicate that diabetes impedes the biosynthetic pathways of 14S,21R-diHDHA in skin wounds. Administration of exogenous 14S,21R-diHDHA to wounds in diabetic animals rescued healing and angiogenesis. When db/db mesenchymal stem cells (MSCs) were administered together with 14S,21R-diHDHA to wounds in diabetic animals, they coacted to accelerate wound re-epithelialization, granulation tissue formation, and synergistically improved vascularization. In the pivotal cellular processes of angiogenesis, 14S,21R-diHDHA enhanced VEGF release, vasculature formation, and migration of db/db dermal microvascular endothelial cells (DMVECs), as well as remedied paracrine angiogenic functions of db/db MSCs, including VEGF secretion and the promotion of DMVEC migration and vasculature formation. Our results show that 14S,21R-diHDHA activates the p38 MAPK pathway in wounds, db/db MSCs, and DMVECs. Overall, the impeded formation of 14S,21R-diHDHA described in this study suggests that diabetes could affect the generation of pro-healing lipid mediators in wound healing. By restoring wound healing and MSC functions, 14S,21R-diHDHA is a new lead for the development of better therapeutics used in treating wounds of diabetics.

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5-Oxo-eicosanoids Are Potent Eosinophil Chemotactic Factors.

Cited by 85 publications

References 28 publications

Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells

Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells

Identification of a Novel Human Eicosanoid Receptor Coupled to Gi/o

14S,21R-Dihydroxydocosahexaenoic Acid Remedies Impaired Healing and Mesenchymal Stem Cell Functions in Diabetic Wounds

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