A novel signaling pathway mediates the inhibition of CCL3/4 expression by prostaglandin E2.
In response to pathogen-associated molecular patterns, dendritic cells initiate an innate immune response characterized by expression and release of proinflammatory cytokines and chemokines. The extent of the inflammatory response is limited by various endogenous factors, including lipid mediators such as prostaglandin E(2) (PGE(2)). We described previously the inhibitory effect of PGE(2) on the expression and release of the inflammatory chemokines CCL3 and CCL4 from activated dendritic cells. In this study we describe a novel PGE(2) signaling pathway that proceeds through EP-2 --> cAMP --> EPAC --> phosphatidylinositol 3-kinase --> protein kinase B --> GSK-3 and results in increased DNA binding of the CCAAT displacement protein (CDP), a potent mammalian transcriptional repressor. The direct link between CDP and CCL3/4 transcription was established in knock-down experiments using CDP small interference RNA.
Jing
Huie
H
Department of Biological Sciences, Rutgers University, 101 Warren Street, Newark, NJ 07102, USA.
Yen
Jui-Hung
JH
Ganea
Doina
D
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D039521:CD11c Antigen / Q000096:biosynthesis; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000502:physiology*; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D018398:Homeodomain Proteins; D007249:Inflammation; D050356:Lipid Metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D051193:Toll-Like Receptors; D014158:Transcription, Genetic
D039521:CD11c Antigen; C496534:Ccl3 protein, mouse; C496535:Ccl4 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines; D019742:Chemokines, CC; C000624101:Cux1 protein, mouse; D016207:Cytokines; D018398:Homeodomain Proteins; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D051193:Toll-Like Receptors; D004247:DNA; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D015232:Dinoprostone