Inflammation is a critical defense mechanism, protecting an organism from pathogens and tumor formation. These processes require tight regulation, and when uncontrolled can result in tissue destruction and contribute to chronic conditions with inflammatory pathogenesis including autoimmune disease, atherosclerosis, asthma, and Alzheimer’s disease. Molecules with important roles in inflammation include proinflammatory leukotrienes and prostaglandins. These are produced from conversion of the omega-6 fatty acid arachidonic acid (AA), via the enzymes cyclooxygenase (COX) and lipoxygenase. In contrast, it has long been known that omega-3 fatty acids enriched in fish oils have beneficial anti-inflammatory properties.1 Similar to AA, the omega-3 fatty acids eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) are substrates for COX and lipoxygenase. Therefore, it has been proposed that EPA and DHA may suppress the pro-inflammatory activities of AA and its metabolites via both competition for the same enzymatic pathway, and the induction of products with lesser inflammatory activity.2 One EPA derivative termed Resolvin E1 (RvE1) has received recent attention, and the discovery of its receptor provides evidence for a novel mechanism underlying its anti-inflammatory activity.
RvE1 was first described in mouse exudates during the resolution phase of inflammation, and is reportedly synthesized in human cells from EPA by a novel transcellular mechanism.3,4 In this proposed pathway, EPA is converted to 18R-Hydroxy-EPA by aspirin-suppressed COX-2 in endothelial cells. This precursor is then transferred to adjacent leukocytes where it is transformed into RvE1 in the presence of 5-lipoxygenase. Administration of RvE1 suppresses leukocyte infiltration, and proinflammatory cytokine and chemokine production in models of colitis and peritonitis.5,6 A new report by Arita et al. suggests that these anti-inflammatory activities may occur via a mechanism that includes RvE1 binding to the cell surface receptor Chem R23.7
Chem R23 is a 7 transmembrane G protein-coupled receptor highly expressed in monocyte-derived antigen-presenting cells (APCs), and to a lesser extent neutrophils and lymphocytes.7,8 Radiolabeled RvE1 binds specifically to Chem R23-transfected CHO cells, but not to mock-transfected controls. It stimulates pertussis toxin-sensitive MAP kinase phosphorylation and NFkB inhibition in Chem R23-transfected HEK cells, indicating a necessary activation of the Gi/o subtype of G protein. Administration of RvE1 suppresses both pathogen-induced dendritic cell IL-12 production and trafficking in spleen. The effects on IL-12 production are inhibited by Chem R23 siRNA, providing strong evidence that RvE1 acts through the Chem R23 receptor.7
