(05-12-09) Resolvin E1 receptor activation signals phosphorylation and phagocytosis.

Ohira T, Arita M, Omori K, Recchiuti A, Van Dyke TE, Serhan CN.
Brigham and Women's Hospital, Harvard Medical School and Boston University, United States;

Resolvins are endogenous lipid mediators that actively regulate the resolution of acute inflammation. Resolvin E1 (RvE1; (5S,12R,18R)-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid) is an endogenous anti-inflammatory and pro-resolving mediator derived from eicosapentaenoic acid that regulates leukocyte migration and enhances macrophage phagocytosis of apoptotic neutrophils to resolve inflammation. In the inflammatory milieu, RvE1 mediates counter-regulatory actions initiated via specific G-protein-coupled receptors (GPCR). Here, we identify RvE1 specific signaling pathways initiated by the RvE1 receptor ChemR23. RvE1 stimulated phosphorylation of Akt that was both ligand and receptor dependent. RvE1 regulated Akt phosphorylation in a time (0-15 min) and dose-dependent (0.01-100 nM) manner in human ChemR23-transfected CHO cells. RvE1 stimulated phosphorylation of both Akt and a 30-kDa protein, a downstream target of Akt, identified using a phospho-Akt substrate antibody. The 30-kDa protein was identified as ribosomal S6 protein, a translational regulator, and its phosphorylation was inhibited by a PI3-K inhibitor (wortmannin) and an ERK inhibitor (PD98059) but not by a p38-MAPK inhibitor (SB203580). Ribosomal S6 protein is a downstream target of the PI3-K/Akt signaling pathway as well as the Raf/ERK pathway. In ChemR23 expressing differentiated HL60 cells, RvE1 also stimulated the phosphorylation of ribosomal S6 protein. In addition, RvE1 enhanced phagocytosis of zymosan A by human macrophages that is inhibited by PD98059 and rapamycin (mTor inhibitor). These results indicate that RvE1 initiates direct activation of ChemR23 and signals receptor dependent phosphorylation. These phosphorylation-signaling pathways identified for RvE1 receptor ligand interactions underscore the importance of endogenous pro-resolving agonists in resolving acute inflammation.

Source: J Biol Chem. 2009 Nov 11

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