title: Prostaglandin E2 Inhibition of IL-27 Production in Murine Dendritic Cells: A Novel Mechanism That Involves IRF1.
abstract: IL-27, a multifunctional cytokine produced by APCs, antagonizes inflammation by affecting conventional dendritic cells (cDC), inducing IL-10, and promoting development of regulatory Tr1 cells. Although the mechanisms involved in IL-27 induction are well studied, much less is known about the factors that negatively impact IL-27 expression. PGE2, a major immunomodulatory prostanoid, acts as a proinflammatory agent in several models of inflammatory/autoimmune disease, promoting primarily Th17 development and function. In this study, we report on a novel mechanism that promotes the proinflammatory function of PGE2We showed previously that PGE2inhibits IL-27 production in murine bone marrow-derived DCs. In this study, we show that, in addition to bone marrow-derived DCs, PGE2inhibits IL-27 production in macrophages and in splenic cDC, and we identify a novel pathway consisting of signaling through EP2/EP4→induction of cAMP→downregulation of IFN regulatory factor 1 expression and binding to the p28 IFN-stimulated response element site. The inhibitory effect of PGE2on p28 and irf1 expression does not involve endogenous IFN-β, STAT1, or STAT2, and inhibition of IL-27 does not appear to be mediated through PKA, exchange protein activated by cAMP, PI3K, or MAPKs. We observed similar inhibition of il27p28 expression in vivo in splenic DC following administration of dimethyl PGE2in conjunction with LPS. Based on the anti-inflammatory role of IL-27 in cDC and through the generation of Tr1 cells, we propose that the PGE2-induced inhibition of IL-27 in activated cDC represents an important additional mechanism for its in vivo proinflammatory functions.
authors.affiliation: Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Hooper
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, IN 46202.
authors.forename: Jui-Hung
authors.identifier: 0000-0002-7325-9756
authors.initials: JH
authors.lastname: Yen
authors.affiliation: Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140.
authors.forename: Weimin
authors.initials: W
authors.lastname: Kong
authors.affiliation: Department of Microbiology and Immunology, University of Illinois College of Medicine at Chicago, Chicago, IL 60612; and.
authors.forename: Kate M
authors.initials: KM
authors.lastname: Rahbari
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, IN 46202.
authors.forename: Ping-Chang
authors.initials: PC
authors.lastname: Kuo
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140.
authors.forename: Ana M
authors.identifier: 0000-0001-7843-1415
authors.initials: AM
authors.lastname: Gamero
authors.affiliation: Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140; doina.ganea@temple.edu.
authors.forename: Doina
authors.initials: D
authors.lastname: Ganea
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D015232:Dinoprostone / Q000008:administration & dosage / Q000276:immunology*; D015536:Down-Regulation; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: C556062:IL10 protein, mouse; C486767:Il27 protein, mouse; D050856:Interferon Regulatory Factor-1; D007378:Interleukins; C494258:Irf1 protein, mouse; C545651:Ptger4 protein, mouse; D058309:Receptors, Prostaglandin E, EP4 Subtype; D016753:Interleukin-10; D000242:Cyclic AMP; D015232:Dinoprostone