Prostaglandin E2 transactivates the colony‐stimulating factor‐1 receptor and synergizes with colony‐stimulating factor‐1 in the induction of macrophage migration via the mitogen‐activated protein kinase ERK1/2

ABSTRACT Prostaglandin E2 (PGE2), a key mediator of immunity, inflammation, and cancer, acts through 4 G‐protein‐coupled E‐prostanoid receptors (EPs 1‐4). Crosstalk between EPs and receptor tyrosine kinases also occurs. Colony‐stimulating factor‐1 receptor (CSF‐1R) is an RTK that sustains the survival, proliferation, and motility of monocytes/macrophages, which are an essential component of innate immunity and cancer development. The aim of this study was to investigate on a possible crosstalk between EP and CSF‐1R. In BAC1.2F5 and RAW264.7 murine macrophages, CSF‐1 (EC50 = 18.1 and 10.2 ng/ml, respectively) and PGE2 (EC50 = 1.5 and 5.5 nM, respectively) promoted migration. PGE2 induced rapid CSF‐1R phosphorylation that was dependent on Src family kinases (SFKs). CSF‐1R inhibition reduced PGE2‐elicited ERK1/2 phosphorylation and macrophage migration, indicating that CSF‐1R plays a role in PGE2‐mediated immunoregulation. EP4 appeared responsible for functional PGE2/CSF‐1R crosstalk. Furthermore, PGE2 synergized with CSF‐1 in inducing ERK1/2 phosphorylation and macrophage migration. ERK1/2 inhibition completely blocked migration induced by the combination CSF‐1/PGE2. CSF‐1/PGE2 functional interaction with respect to migration also occurred in bone marrow‐derived murine macrophages (EC50 CSF‐1, 6.7 ng/ml; EC50 PGE2, 16.7 nM). These results indicated that PGE2 transactivates CSF‐1R and synergizes with its signaling at ERK1/2 level in promoting macrophage migration.—Digiacomo, G., Ziche, M., Sbarba, P. D., Donnini, S., Rovida, E. Prostaglandin E2 transactivates the colony‐stimulating factor‐1 receptor and synergizes with colony‐stimulating factor‐1 in the induction of macrophage migration via the mitogen‐activated protein kinase ERK1/21. FASEB J. 29, 2545‐2554 (2015). www.fasebj.org