Prostaglandin E2 promotes M2 polarization of macrophages via a cAMP/CREB signaling pathway and deactivates granulocytes in teleost fish

The profile of prostaglandin (PG) production is determined by the differential expression of the enzymes involved in their production and degradation. Although the production of PGE(2) by fish leukocytes has been relatively well studied in several fish species, knowledge of how its production is regulated, its biological activities and the signaling pathways activated by this PG is scant or even contradictory. In this work we show that in the teleost fish gilthead seabream (Sparus aurata L) macrophages regulate PGE(2) release mainly by inducing the expression of the genes encoding the enzymes responsible for its synthesis, while acidophilic granulocytes (AGs) not only induce these genes quickly after activation but also inhibit the expression of the genes encoding the enzymes responsible for PGE(2) degradation at later time points. In addition, treatment of macrophages with PGE(2) promoted their M2 polarization, which is characterized by high expression levels of interleukin-10, mannose-receptor c-type 1 and arginase 2 genes. In sharp contrast, PGE(2) promoted the deactivation of AGs, since it decreased the production of reactive oxygen species and the expression of genes encoding pro-inflammatory cytokines. These differences are the result of the alternative signaling pathways used by PGE(2) in macrophages and AGs, a cAMP/CREB signaling pathway operating in macrophages, but not in AGs, downstream of PGE(2). Our data identify for the first time a role for professional phagocyte-derived-PGE(2) in the resolution of inflammation in fish and highlight key differences in the PGE(2) signaling pathway in macrophages and granulocytes. (C) 2016 Elsevier Ltd. All rights reserved.