Highlights
- •5-lipoxygenase (5-LO) catalyzes the conversion of 20:4 n-3 into novel oxygenated metabolites.
- •Metabolites identified as Δ17-8‑hydroxy‑eicosatetraenoic acid (Δ17-8-HETE) and Δ17-8,15-dihydroxy-eicosatetraenoic acid (Δ17-8,15-diHETE).
- •Δ17-8,15-diHETE biosynthesis is inhibited by LTA4 hydrolase inhibitor SC 57461A.
- •Δ17-8,15-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 (Δ17-8-HETE) and 8,15-dihydroxy-9,11,13,17-eicosatetraenoic acid (Δ17-8,15-diHETE) were identified as novel metabolites. Δ17-8,15-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 Δ17-8,15-diHETE at low nM concentrations. These data support an anti-inflammatory role
for Δ17-8,15-diHETE, a novel 5-LO product.
Keywords
- 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
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Article info
Publication history
Published online: October 15, 2018
Accepted:
October 13,
2018
Received in revised form:
October 4,
2018
Received:
August 14,
2018
Identification
Copyright
© 2018 Elsevier Ltd. All rights reserved.
