title: CD40 engagement on dendritic cells induces cyclooxygenase-2 and EP2 receptor via p38 and ERK MAPKs.
abstract: We have previously reported that cyclooxygenase (COX)-2-derived prostaglandin (PG)E2 critically regulates dendritic cell (DC) inflammatory phenotype and function through EP2/EP4 receptor subtypes. As genes activated by CD40 engagement are directly relevant to inflammation, we examined the effects of CD40 activation on inflammatory PGs in murine bone marrow-derived DC (mBM-DC). We showed for the first time that activation of mBM-DC with agonist anti-CD40 monoclonal antibody (anti-CD40 mAb) dose dependently induces the synthesis of significant amounts of PGE2 via inducible expression of COX-2 enzyme, as NS-398, a COX-2-selective inhibitor reduces this upregulation. In contrast to lipopolysaccharide, which upregulates mBM-DC surface levels of EP2 and EP4 receptors, CD40 crosslinking on mBM-DC increases EP2, but not EP4, receptor expression. Flow cytometry analysis and radioligand-binding assay showed that EP2 was the major EP receptor subtype, which binds to PGE2 at the surface of anti-CD40-activated mBM-DC. Upregulation of COX-2 and EP2 levels by CD40 engagement was accompanied by dose-dependent phosphorylation of p38 and ERK1/2 mitogen-activated protein kinase (MAPK) and was abrogated by inhibitors of both pathways. Collectively, we demonstrated that CD40 engagement on mBM-DC upregulates COX-2 and EP2 receptor expression through activation of p38 and ERK1/2 MAPK signaling. Triggering the PGE2/EP2 pathway by anti-CD40 mAb resulted on the induction of Th2 immune response. Thus, CD40-induced production of PGE2 by mBM-DC could represent a negative feedback mechanism involving EP2 receptor and limiting the propagation of Th1 responses. Blocking CD40 pathway may represent a novel therapeutic pathway of inhibiting COX-2-derived prostanoids in chronically inflamed tissues (that is, arthritis).
authors.affiliation: CNRS UMR 5540, Bordeaux, Université Bordeaux 2, Bordeaux, France. hharizi@hotmail.fr
authors.forename: Hedi
authors.initials: H
authors.lastname: Harizi
authors.forename: Ilef
authors.initials: I
authors.lastname: Limem
authors.forename: Norbert
authors.initials: N
authors.lastname: Gualde
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology; D019013:CD40 Antigens / Q000819:agonists / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D015232:Dinoprostone / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D007109:Immunity / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone