1. 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
- Author
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Miguel G. Toscano, Doina Ganea, Sabina Adhikary, Jui-Hung Yen, Frances A. Emig, and Virginia Kocieda
- Subjects
Lipopolysaccharides ,Male ,CAMP Responsive Element Binding Protein ,Transcription, Genetic ,Immunology ,EP4 Receptor ,Bone Marrow Cells ,CREB ,Second Messenger Systems ,Biochemistry ,Dinoprostone ,Mice ,Enhancer binding ,Cyclic AMP ,Animals ,Guanine Nucleotide Exchange Factors ,Alprostadil ,Binding site ,Cyclic AMP Response Element-Binding Protein ,Promoter Regions, Genetic ,Protein kinase A ,Molecular Biology ,Transcription factor ,Cells, Cultured ,Binding Sites ,biology ,Tumor Necrosis Factor-alpha ,CCAAT-Enhancer-Binding Protein-beta ,Toll-Like Receptors ,Dendritic Cells ,Cell Biology ,Cyclic AMP-Dependent Protein Kinases ,Interleukin-12 ,Molecular biology ,Up-Regulation ,Mice, Inbred C57BL ,Gene Expression Regulation ,Interleukin-23 Subunit p19 ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Signal transduction ,Receptors, Prostaglandin E, EP4 Subtype ,Adenylyl Cyclases ,Protein Binding - 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.
- Published
- 2012
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