Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation.
Resolvin E1 (RvE1) is a potent anti-inflammatory and proresolving mediator derived from omega-3 eicosapentaenoic acid generated during the resolution phase of inflammation. RvE1 possesses a unique structure and counterregulatory actions that stop human polymorphonuclear leukocyte (PMN) transendothelial migration and PMN infiltration in several murine inflammatory models. To examine the mechanism(s) underlying anti-inflammatory actions on PMNs, we prepared [(3)H]RvE1 and characterized its interactions with human PMN. Results with membrane fractions of human PMN demonstrated specific binding with a K(d) of 48.3 nM. [(3)H]RvE1 specific binding to human PMN was displaced by leukotriene B(4) (LTB(4)) and LTB(4) receptor 1 (BLT1) antagonist U-75302, but not by chemerin peptide, a ligand specific for another RvE1 receptor ChemR23. Recombinant human BLT1 gave specific binding with [(3)H]RvE1 with a K(d) of 45 nM. RvE1 selectively inhibited adenylate cyclase with BLT1, but not with BLT2. In human PBMC, RvE1 partially induced calcium mobilization, and blocked subsequent stimulation by LTB(4). RvE1 also attenuated LTB(4)-induced NF-kappaB activation in BLT1-transfected cells. In vivo anti-inflammatory actions of RvE1 were sharply reduced in BLT1 knockout mice when given at low doses (100 ng i.v.) in peritonitis. In contrast, RvE1 at higher doses (1.0 mug i.v.) significantly reduced PMN infiltration in a BLT1-independent manner. These results indicate that RvE1 binds to BLT1 as a partial agonist, potentially serving as a local damper of BLT1 signals on leukocytes along with other receptors (e.g., ChemR23-mediated counterregulatory actions) to mediate the resolution of inflammation.
Arita
Makoto
M
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
Ohira
Taisuke
T
Sun
Yee-Ping
YP
Elangovan
Siva
S
Chiang
Nan
N
Serhan
Charles N
CN
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D018925:Chemokines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D005233:Fatty Alcohols / Q000494:pharmacology; D006018:Glycols / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D019707:Receptors, Chemokine / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism
C102741:CMKLR1 protein, human; D018925:Chemokines; D005233:Fatty Alcohols; D006018:Glycols; D036341:Intercellular Signaling Peptides and Proteins; C513240:LTB4R protein, human; D008024:Ligands; C503704:Ltb4r1 protein, mouse; D010455:Peptides; C478630:RARRES2 protein, human; D019707:Receptors, Chemokine; D018102:Receptors, Leukotriene B4; C062137:U 75302; D015118:Eicosapentaenoic Acid; C499823:5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid