title: Identification and structure determination of novel anti-inflammatory mediator resolvin E3, 17,18-dihydroxyeicosapentaenoic acid.
abstract: Bioactive mediators derived from omega-3 eicosapentaenoic acid (EPA) elicit potent anti-inflammatory actions. Here, we identified novel EPA metabolites, including 8,18-dihydroxyeicosapentaenoic acid (8,18-diHEPE), 11,18-diHEPE, 12,18-diHEPE, and 17,18-diHEPE from 18-HEPE. Unlike resolvins E1 and E2, both of which are biosynthesized by neutrophils via the 5-lipoxygenase pathway, these metabolites are biosynthesized by eosinophils via the 12/15-lipoxygenase pathway. Among them, two stereoisomers of 17,18-diHEPE, collectively termed resolvin E3 (RvE3), displayed a potent anti-inflammatory action by limiting neutrophil infiltration in zymosan-induced peritonitis. The planar structure of RvE3 was unambiguously determined to be 17,18-dihydroxy-5Z,8Z,11Z,13E,15E-EPE by high resolution NMR, and the two stereoisomers were assigned to have 17,18R- and 17,18S-dihydroxy groups, respectively, using chemically synthesized 18R- and 18S-HEPE as precursors. Both 18R- and 18S-RvE3 inhibited neutrophil chemotaxis in vitro at low nanomolar concentrations. These findings suggest that RvE3 contributes to the beneficial actions of EPA in controlling inflammation and related diseases.
authors.affiliation: Departments of Health Chemistry, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033; Business-Academia-Collaborative Laboratory, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Isobe
authors.affiliation: Departments of Health Chemistry, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033; PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, Japan. Electronic address: marita@mol.f.u-tokyo.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Arita
authors.affiliation: Departments of Health Chemistry, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
authors.forename: Shinnosuke
authors.initials: S
authors.lastname: Matsueda
authors.affiliation: Business-Academia-Collaborative Laboratory, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
authors.forename: Ryo
authors.initials: R
authors.lastname: Iwamoto
authors.affiliation: Business-Academia-Collaborative Laboratory, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033; Shionogi Research Laboratories, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, and.
authors.forename: Takuji
authors.initials: T
authors.lastname: Fujihara
authors.affiliation: Department of Metabolome, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nakanishi
authors.affiliation: Department of Metabolome, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
authors.forename: Ryo
authors.initials: R
authors.lastname: Taguchi
authors.affiliation: Business-Academia-Collaborative Laboratory, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033; Shionogi Research Laboratories, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, and.
authors.forename: Koji
authors.initials: K
authors.lastname: Masuda
authors.affiliation: Departments of Integral Analytical Chemistry, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sasaki
authors.affiliation: Departments of Integral Analytical Chemistry, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Urabe
authors.affiliation: Departments of Integral Analytical Chemistry, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Departments of Health Chemistry, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
mesh_terms: D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D004804:Eosinophils / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D009504:Neutrophils / Q000378:metabolism*; D010538:Peritonitis / Q000139:chemically induced / Q000378:metabolism*; D015054:Zymosan / Q000633:toxicity
chemical_list: D018836:Inflammation Mediators; D004281:Docosahexaenoic Acids; D015054:Zymosan; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase