title: Prostaglandin E2 restrains macrophage maturation via E prostanoid receptor 2/protein kinase A signaling.
abstract: Prostaglandin E(2) (PGE(2)) is a lipid mediator that acts by ligating 4 distinct G protein-coupled receptors, E prostanoid (EP) 1 to 4. Previous studies identified the importance of PGE(2) in regulating macrophage functions, but little is known about its effect on macrophage maturation. Macrophage maturation was studied in vitro in bone marrow cell cultures, and in vivo in a model of peritonitis. EP2 was the most abundant PGE(2) receptor expressed by bone marrow cells, and its expression further increased during macrophage maturation. EP2-deficient (EP2(-/-)) macrophages exhibited enhanced in vitro maturation compared with wild-type cells, as evidenced by higher F4/80 expression. An EP2 antagonist also increased maturation. In the peritonitis model, EP2(-/-) mice exhibited a higher percentage of F4/80(high)/CD11b(high) cells and greater expression of macrophage colony-stimulating factor receptor (M-CSFR) in both the blood and the peritoneal cavity. Subcutaneous injection of the PGE(2) analog misoprostol decreased M-CSFR expression in bone marrow cells and reduced the number of peritoneal macrophages in wild-type mice but not EP2(-/-) mice. The suppressive effect of EP2 ligation on in vitro macrophage maturation was mimicked by a selective protein kinase A agonist. Our findings reveal a novel role for PGE(2)/EP2/protein kinase A signaling in the suppression of macrophage maturation.
authors.affiliation: Divisions of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, USA.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Zaslona
authors.forename: Carlos H
authors.initials: CH
authors.lastname: Serezani
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Okunishi
authors.forename: David M
authors.initials: DM
authors.lastname: Aronoff
authors.forename: Marc
authors.initials: M
authors.lastname: Peters-Golden
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016595:Misoprostol / Q000494:pharmacology; D010538:Peritonitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013864:Thioglycolates; D044004:Xanthones / Q000494:pharmacology
chemical_list: D000943:Antigens, Differentiation; D039481:CD11b Antigen; D011448:Prostaglandin Antagonists; D058307:Receptors, Prostaglandin E, EP2 Subtype; D013864:Thioglycolates; D044004:Xanthones; C036763:monocyte-macrophage differentiation antigen; D016595:Misoprostol; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone