title: Prostaglandin E2-induced IL-23p19 subunit is regulated by cAMP-responsive element-binding protein and C/AATT enhancer-binding protein β in bone marrow-derived dendritic cells.
abstract: We reported previously that prostaglandin E2 (PGE2) up-regulates IL-23 in vitro in bone marrow-derived dendritic cells and in vivo in models of collagen-induced arthritis and inflammatory bowel disease, leading to preferential Th17 development and activity. There is very little information on the molecular mechanisms involved in the PGE2-induced up-regulation of Il23a gene expression. In this study we investigated the signaling pathways and transcription factors involved in the stimulatory effect of PGE2. Although PGE2 does not induce IL-23p19 expression by itself, it synergizes with both extra- and intracellular Toll-like receptor ligands and with inflammatory cytokines such as TNFα. We established that the effect of PGE2 in conjunction with either LPS or TNFα is mediated through the EP4 receptor and the cAMP-dependent activation of both protein kinase A (PKA) and exchange protein activated by cAMP (EPAC). Using the EP4 agonist PGE(1)OH in conjunction with TNFα, we found that PKA-induced phosphorylation of cAMP-response element-binding protein ((P)CREB) and EPAC-induced phosphorylation of C/AATT enhancer-binding protein β ((P)C/EBPβ) mediate the stimulatory effect of PGE2 on IL-23p19 expression. This is the first report of CREB and C/EBPβ involvement in Il23a promoter activation. Mutation within the putative CREB and C/EBP sites combined with in vivo DNA binding (ChIP) assays identified the distal CREB site (-1125) and the two proximal C/EBP sites (-274 and -232) as essential for PKA-activated CREB and EPAC-activated C/EBPβ-induced IL-23p19 expression.
authors.affiliation: Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Virginia P
authors.initials: VP
authors.lastname: Kocieda
authors.forename: Sabina
authors.initials: S
authors.lastname: Adhikary
authors.forename: Frances
authors.initials: F
authors.lastname: Emig
authors.forename: Jui-Hung
authors.initials: JH
authors.lastname: Yen
authors.forename: Miguel G
authors.initials: MG
authors.lastname: Toscano
authors.forename: Doina
authors.initials: D
authors.lastname: Ganea
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D015232:Dinoprostone / Q000502:physiology*; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D015290:Second Messenger Systems; D051193:Toll-Like Receptors / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D015854:Up-Regulation
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C545013:Cebpb protein, mouse; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D053760:Interleukin-23 Subunit p19; D008070:Lipopolysaccharides; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D000527:Alprostadil; C048491:butaprost; D015232:Dinoprostone