title: Endogenous prostaglandin E2 potentiates anti-inflammatory phenotype of macrophage through the CREB-C/EBP-β cascade.
abstract: Macrophages have important functions in tissue homeostasis, but the exact mechanisms regarding wide spectrum of macrophage phenotype remain unresolved. In this study, we report that mouse bone marrow derived naïve macrophages produce prostaglandin E2 (PGE2 ) endogenously, resulting in anti-inflammatory gene expression upon differentiation induced by macrophage colony stimulating factor (M-CSF). Cyclooxygenase (COX) inhibition by indomethacin reduced endogenous PGE2 production of macrophages and subsequently reduced arg1, IL10 and Mrc1, YmI and FizzI gene expressions. Of note, PGE2 phosphorylates CREB via EP2 and EP4 receptor ligation, thereby transcriptionally increasing C/EBP-β expression in BALB/c bone marrow derived macrophages. Activated CREB directly binds to the CREB-responsive element of the C/EBP-β promoter, such that PGE2 ultimately reinforces arg1, IL10 and Mrc1 gene expression. Cyclic AMP activator forskolin also phosphorylated CREB and induced the C/EBP-β cascade, but this was completely blocked by the PKA inhibitor, H89. Consequently, M-CSF grown macrophages inhibited T-cell proliferation but the inhibition ability was reduced when the COX is inhibited by indomethacin or macrophage C/EBP-β expression was decreased by siRNA transduction. Our results collectively describe the molecular basis for homeostatic macrophage differentiation by endogenous PGE2 .
authors.affiliation: Macrophage Laboratory, Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Yi Rang
authors.initials: YR
authors.lastname: Na
authors.affiliation: Macrophage Laboratory, Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Daun
authors.initials: D
authors.lastname: Jung
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Bo Ruem
authors.initials: BR
authors.lastname: Yoon
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, South Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Won Woo
authors.initials: WW
authors.lastname: Lee
authors.affiliation: Macrophage Laboratory, Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Seung Hyeok
authors.initials: SH
authors.lastname: Seok
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000276:immunology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000276:immunology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015232:Dinoprostone / Q000096:biosynthesis*; D005260:Female; D005786:Gene Expression Regulation; D007213:Indomethacin / Q000494:pharmacology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D007546:Isoquinolines / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D061251:Primary Cell Culture; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C545013:Cebpb protein, mouse; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C556062:IL10 protein, mouse; D007546:Isoquinolines; C581013:MRC1 protein, mouse; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D013449:Sulfonamides; D016753:Interleukin-10; D005576:Colforsin; D016173:Macrophage Colony-Stimulating Factor; D011451:Prostaglandin-Endoperoxide Synthases; D017868:Cyclic AMP-Dependent Protein Kinases; C544448:Arg1 protein, mouse; D001119:Arginase; D015232:Dinoprostone; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D007213:Indomethacin
keywords: C/EBP-β; CREB; Homeostasis; Macrophages; Prostaglandin E2