4.6 Article

Identification and Structure Determination of Novel Anti-inflammatory Mediator Resolvin E3, 17,18-Dihydroxyeicosapentaenoic Acid

Journal

JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 287, Issue 13, Pages 10525-10534

Publisher

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.340612

Keywords

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Funding

  1. Japan Science and Technology Agency Precursory Research for Embryonic Science and Technology
  2. Core Research for Evolutional Science and Technology
  3. Ministry of Education, Culture, Sports, Science, and Technology of Japan
  4. Ono Medical Research Foundation
  5. Program for Promotion of Basic and Applied Research for Innovations in Bio-Oriented industry
  6. Grants-in-Aid for Scientific Research [22116006, 23790074, 22116001, 21370051, 23227004, 23790005] Funding Source: KAKEN

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Bioactive mediators derived from omega-3 eicosapentaenoic acid (EPA) elicit potent anti-inflammatory actions. Here, we identified novel EPA metabolites, including 8,18-dihydroxyei-cosapentaenoic 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.

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