title: A role for 12R-lipoxygenase in MUC5AC expression by respiratory epithelial cells.
abstract: Eicosanoids are metabolites of arachidonic acid produced by cyclooxygenases (COXs) or lipoxygenases (LOXs). They mediate inflammation and mucus secretion in chronic pulmonary inflammatory diseases. The gel-forming mucin MUC5AC is over-expressed in the airways of patients with these diseases. MUC5AC expression is mediated by an extracellular signal-regulated kinase (ERK)/Sp1 dependent mechanism. Our aim was to study the role of eicosanoids and their signalling pathways in MUC5AC expression. Inhibitors of 12-LOX, but not those of COX, 5-LOX or 15-LOX, reduce MUC5AC expression induced by phorbol myristate acetate (PMA) in the bronchial epithelial cell line NCI-H292. These inhibitors also abrogate the production of whole mucus by cell monolayers. Two forms of 12-LOX (R and S) exist in mammals. Using siRNAs we show that 12R-LOX but not 12S-LOX is involved in MUC5AC expression induced by PMA, lipopolysaccharide or transforming growth factor-α. 12R-LOX also participates in MUC2 and MUC5B expression, although to a lesser extent than for MUC5AC. Contrarily, 12R-LOX silencing does not modify interleukin-8 production. 12-LOX inhibitors reduce ERK activation and Sp1 translocation induced by PMA. Moreover, the 12R-LOX product 12(R)-hydroxyeicosatetraenoic acid, induces MUC5AC expression, ERK activation and Sp1 translocation. 12R-LOX is involved in MUC5AC expression. This occurs via ERK- and Sp1-signalling pathways.
authors.affiliation: Unité de Défense Innée et Inflammation Institut Pasteur, INSERM U874, 25 rue Dr Roux, 75015 Paris, France. ignacio.garcia-verdugo@pasteur.fr
authors.forename: Ignacio
authors.initials: I
authors.lastname: Garcia-Verdugo
authors.forename: Fatima
authors.initials: F
authors.lastname: BenMohamed
authors.forename: Sonja
authors.initials: S
authors.lastname: Tattermusch
authors.forename: Dominique
authors.initials: D
authors.lastname: Leduc
authors.forename: Gilles
authors.initials: G
authors.lastname: Charpigny
authors.forename: Michel
authors.initials: M
authors.lastname: Chignard
authors.forename: Mario
authors.initials: M
authors.lastname: Ollero
authors.forename: Lhousseine
authors.initials: L
authors.lastname: Touqui
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D002273:Carcinogens / Q000494:pharmacology; D002460:Cell Line; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D055271:Mucin 5AC / Q000096:biosynthesis*; D055262:Mucin-2 / Q000096:biosynthesis; D055257:Mucin-5B / Q000096:biosynthesis; D009093:Mucus / Q000378:metabolism; D021381:Protein Transport; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016211:Transforming Growth Factor alpha / Q000494:pharmacology
chemical_list: C508606:CXCL8 protein, human; D002273:Carcinogens; D016861:Cyclooxygenase Inhibitors; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; C524625:MUC2 protein, human; C524678:MUC5AC protein, human; C524578:MUC5B protein, human; D055271:Mucin 5AC; D055262:Mucin-2; D055257:Mucin-5B; D016329:Sp1 Transcription Factor; D016211:Transforming Growth Factor alpha; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001092:Arachidonate 12-Lipoxygenase; C476558:ALOX12 protein, human; D013755:Tetradecanoylphorbol Acetate