Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1.
The essential fatty acid eicosapentaenoic acid (EPA) present in fish oils displays beneficial effects in a range of human disorders associated with inflammation including cardiovascular disease. Resolvin E1 (RvE1), a new bioactive oxygenated product of EPA, was identified in human plasma and prepared by total organic synthesis. Results of bioaction and physical matching studies indicate that the complete structure of RvE1 is 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-EPA. At nanomolar levels, RvE1 dramatically reduced dermal inflammation, peritonitis, dendritic cell (DC) migration, and interleukin (IL) 12 production. We screened receptors and identified one, denoted earlier as ChemR23, that mediates RvE1 signal to attenuate nuclear factor-kappaB. Specific binding of RvE1 to this receptor was confirmed using synthetic [(3)H]-labeled RvE1. Treatment of DCs with small interference RNA specific for ChemR23 sharply reduced RvE1 regulation of IL-12. These results demonstrate novel counterregulatory responses in inflammation initiated via RvE1 receptor activation that provide the first evidence for EPA-derived potent endogenous agonists of antiinflammation.
Arita
Makoto
M
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Bianchini
Francesca
F
Aliberti
Julio
J
Sher
Alan
A
Chiang
Nan
N
Hong
Song
S
Yang
Rong
R
Petasis
Nicos A
NA
Serhan
Charles N
CN
D000595:Amino Acid Sequence; D000818:Animals; D003713:Dendritic Cells / Q000378:metabolism; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010802:Phylogeny; D011869:Radioligand Assay; D019707:Receptors, Chemokine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism
C102741:CMKLR1 protein, human; D015525:Fatty Acids, Omega-3; D008024:Ligands; D019707:Receptors, Chemokine; D015118:Eicosapentaenoic Acid; C499823:5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid