5-lipoxygenase-dependent biosynthesis of novel 20:4 n-3 metabolites with anti-inflammatory activity. (November 2018)

• Record Type: Journal Article
• Authors: Gagnon, K.J.; Lefort, N.; Poirier, S.J.; Barnett, D.A.; Surette, M.E.
• Is Part Of: Prostaglandins, leukotrienes, and essential fatty acids. Volume 138(2018)
• Page Start: 38
• Page End: 44
• Publication Date: 2018-11
• Subjects: Leukotrienes -- Lipid mediators -- Inflammation -- Neutrophils -- Eicosanoids; Abbreviations: 19-OH-PGB2, 19(R)-hydroxy-prostaglandin B2 -- AA, arachidonic acid -- ADA, adenosine deaminase -- ALA, alpha-linolenic acid -- BLT1, leukotriene B4 receptor 1 -- DHA, docosahexaenoic acid -- DPA, docosapentaenoic acid -- ETA, eicosatetraenoic acid -- EtOH, ethanol -- HpETE, hydroperoxyeicosatetraenoic acid -- LO, lipoxygenase -- LTA4, leukotriene A4 -- LTB4, leukotriene B4 -- LTC4, leukotriene C4 -- MeOH, methanol -- NEM, N-ethylmaleimide -- RP-HPLC, reverse phase-HPLC -- SDA, stearidonic acid; Lipids -- Periodicals; Unsaturated fatty acids -- Periodicals; Prostaglandins -- Periodicals; Leukotrienes -- Periodicals; Fatty Acids, Unsaturated -- Periodicals; Acides gras insaturés -- Périodiques; Prostaglandines -- Périodiques; Leucotriènes -- Périodiques; Lipides -- Périodiques; 612.01577
• DOI: 10.1016/j.plefa.2018.10.005
• Languages: English
• ISSNs: 0952-3278

Abstract

Highlights: 5-lipoxygenase (5-LO) catalyzes the conversion of 20:4 n-3 into novel oxygenated metabolites. Metabolites identified as Δ 17 -8‑hydroxy‑eicosatetraenoic acid (Δ 17 -8-HETE) and Δ 17 -8, 15-dihydroxy-eicosatetraenoic acid (Δ 17 -8, 15-diHETE). Δ 17 -8, 15-diHETE biosynthesis is inhibited by LTA4 hydrolase inhibitor SC 57461A. Δ 17 -8, 15-diHETE inhibits arachidonic acid-induced autocrine neutrophil stimulation and LTB4 -induced neutrophil chemotaxis. Abstract: 5-lipoxygenase (5-LO) catalyzes the conversion of arachidonic acid (AA) into pro-inflammatory leukotrienes. N-3 PUFA like eicosapentaenoic acid are subject to a similar metabolism and are precursors of pro-resolving mediators. Stearidonic acid (18:4 n-3, SDA) is a plant source of n-3 PUFA that is elongated to 20:4 n-3, an analogue of AA. However, no 5-LO metabolites of 20:4 n-3 have been reported. In this study, control and 5-LO-expressing HEK293 cells were stimulated in the presence of 20:4 n-3. Metabolites were characterized by LC-MS/MS and their anti-inflammatory properties assessed using AA-induced autocrine neutrophil stimulation and leukotriene B4 -mediated chemotaxis. 8‑hydroxy‑9, 11, 14, 17-eicosatetraenoic acid (Δ 17 -8-HETE) and 8, 15-dihydroxy-9, 11, 13, 17-eicosatetraenoic acid (Δ 17 -8, 15-diHETE) were identified as novel metabolites. Δ 17 -8, 15-diHETE production was inhibited by the leukotriene A4 hydrolase inhibitor SC 57461A. Autocrine neutrophil leukotriene stimulation and neutrophil chemotaxis, both BLT1-dependent processes, were inhibited by Δ 17 -8, 15-diHETE at low nM concentrations. These data support an anti-inflammatory role for Δ 17 -8, 15-diHETE, a novel 5-LO product.