title: Prostaglandin E2 induces matrix metalloproteinase 9 expression in dendritic cells through two independent signaling pathways leading to activator protein 1 (AP-1) activation.
abstract: Dendritic Cells (DCs) play an important role in the initiation of the immune response by migrating to regional lymph nodes and presenting antigen processed at the inflammatory site to antigen-specific naïve T cells. Prostaglandin E2 (PGE2) has been reported to play an essential role in DC migration. We reported previously that PGE2 induces matrix metalloproteinase 9 (MMP-9) expression in DCs and that PGE2-induced MMP-9 is required for DC migration in vivo and in vitro. In this study, we investigated the signaling mechanisms involved in PGE2-induced MMP-9 expression in DCs. We show that PGE2-induced MMP-9 expression is mediated primarily through the EP2/EP4 → cAMP → protein kinase A (PKA)/PI3K → ERK signaling pathway, leading to c-Fos expression, and through JNK-mediated activation of c-Jun in a PKA/PI3K/ERK-independent manner. EP2 and EP4 receptor agonists, as well as cAMP analogs, mimic the up-regulation of MMP-9 by PGE2. PKA, PI3K, and ERK inhibitors abolished PGE2- and cAMP-induced c-Fos and MMP-9 up-regulation, and ERK activation was required for the binding of activator protein 1 (AP-1) transcription factor to the MMP-9 promoter. Our results describe a new molecular mechanism for the effect of PGE2 on MMP-9 production in DCs that could lead to future therapeutic approaches using ERK inhibitors to regulate DC migration.
authors.affiliation: Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Jui-Hung
authors.initials: JH
authors.lastname: Yen
authors.forename: Virginia P
authors.initials: VP
authors.lastname: Kocieda
authors.forename: Huie
authors.initials: H
authors.lastname: Jing
authors.forename: Doina
authors.initials: D
authors.lastname: Ganea
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D018808:Transcription Factor AP-1; D000242:Cyclic AMP; D011494:Protein Kinases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D015232:Dinoprostone