title: 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.
authors.affiliation: *Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", Università degli Studi di Firenze, Florence, Italy; Dipartimento di Scienze della Vita, Università degli Studi di Siena, Siena, Italy; and Istituto Toscano Tumori, Florence, Italy.
authors.forename: Graziana
authors.initials: G
authors.lastname: Digiacomo
authors.affiliation: *Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", Università degli Studi di Firenze, Florence, Italy; Dipartimento di Scienze della Vita, Università degli Studi di Siena, Siena, Italy; and Istituto Toscano Tumori, Florence, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Ziche
authors.affiliation: *Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", Università degli Studi di Firenze, Florence, Italy; Dipartimento di Scienze della Vita, Università degli Studi di Siena, Siena, Italy; and Istituto Toscano Tumori, Florence, Italy.
authors.forename: Persio
authors.initials: P
authors.lastname: Dello Sbarba
authors.affiliation: *Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", Università degli Studi di Firenze, Florence, Italy; Dipartimento di Scienze della Vita, Università degli Studi di Siena, Siena, Italy; and Istituto Toscano Tumori, Florence, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Donnini
authors.affiliation: *Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio", Università degli Studi di Firenze, Florence, Italy; Dipartimento di Scienze della Vita, Università degli Studi di Siena, Siena, Italy; and Istituto Toscano Tumori, Florence, Italy erovida@unifi.it.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Rovida
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D015232:Dinoprostone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015151:Immunoblotting; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000187:drug effects; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015232:Dinoprostone
keywords: cytokine receptors; inflammation; monocytes/macrophages; signal transduction