Identification and structure determination of novel anti-inflammatory mediator resolvin E3, 17,18-dihydroxyeicosapentaenoic acid

J Biol Chem. 2012 Mar 23;287(13):10525-34. doi: 10.1074/jbc.M112.340612. Epub 2012 Jan 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arachidonate 12-Lipoxygenase / metabolism*
  • Arachidonate 15-Lipoxygenase / metabolism*
  • Docosahexaenoic Acids / metabolism*
  • Eosinophils / metabolism*
  • Female
  • HEK293 Cells
  • Humans
  • Inflammation Mediators / metabolism*
  • Magnetic Resonance Spectroscopy
  • Male
  • Molecular Structure
  • Neutrophils / metabolism*
  • Peritonitis / chemically induced
  • Peritonitis / metabolism*
  • Zymosan / toxicity

Substances

  • Inflammation Mediators
  • Docosahexaenoic Acids
  • Zymosan
  • Arachidonate 12-Lipoxygenase
  • Arachidonate 15-Lipoxygenase