title: Evidence for a role of phosphodiesterase 4 in lipopolysaccharide-stimulated prostaglandin E2 production and matrix metalloproteinase-9 activity in human amniochorionic membranes.
abstract: Chorioamniotic infection is a leading cause of preterm premature rupture of fetal membranes (amnion and chorion). Bacterial infection induces an inflammatory response characterized by elevated production of proinflammatory cytokines; the latter activate the production of both PGs that stimulate uterine contractions, and matrix metalloproteinases (MMPs) that degrade the extracellular matrix of the chorioamniotic membranes. The inflammatory response is under the control of cAMP content, which is partly regulated by phosphodiesterases (PDE). In this study, we investigated the role of the PDE4 family in the inflammatory process triggered by LPS in a model of amniochorionic explants. We found that PDE4 family is the major cAMP-PDE expressed in human fetal membranes and that PDE4 activity is increased by LPS treatment. Selective inhibition of PDE4 activity affected LPS signaling, because PDE4 inhibitors (rolipram and/or cilomilast) reduced the release of the proinflammatory cytokine TNF-alpha and increased the release of the anti-inflammatory cytokine IL-10. PDE4 inhibition reduced cyclooxygenase-2 protein expression and PGE(2) production and also modulated MMP-9, a key mediator of the membrane rupture process, by inhibiting pro-MMP-9 mRNA expression and pro-MMP-9 activity. These results demonstrate that the PDE4 family participates in the regulation of the inflammatory response associated with fetal membrane rupture during infection. The PDE4 family may be an appropriate pharmacological target for the management of infection-induced preterm delivery.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 427, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Oger
authors.forename: Céline
authors.initials: C
authors.lastname: Méhats
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Dallot
authors.forename: Dominique
authors.initials: D
authors.lastname: Cabrol
authors.forename: Marie-Josèphe
authors.initials: MJ
authors.lastname: Leroy
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000502:physiology; D000650:Amnion / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D002823:Chorion / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000502:physiology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004792:Enzyme Precursors / Q000378:metabolism; D005260:Female; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008565:Membrane Proteins; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D020889:Rolipram / Q000494:pharmacology; D046509:Tissue Culture Techniques; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D004792:Enzyme Precursors; D007106:Immune Sera; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020780:Matrix Metalloproteinase 9; D020889:Rolipram; D015232:Dinoprostone