Preferential Generation of 15-HETE-PE Induced by IL-13 Regulates Goblet Cell Differentiation in Human Airway Epithelial Cells

• Published in: American journal of respiratory cell and molecular biology Vol. 57; no. 6; pp. 692 - 701
• Main Authors: Zhao, Jinming, Minami, Yoshinori, Etling, Emily, Coleman, John M., Lauder, Sarah N., Tyrrell, Victoria, Aldrovandi, Maceler, O’Donnell, Valerie, Claesson, Hans-Erik, Kagan, Valerian, Wenzel, Sally
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.12.2017
• Subjects: Airway Remodeling - drug effects; Arachidonate 15-Lipoxygenase - metabolism; Arachidonic acid; Asthma; Cell culture; Cell Differentiation - drug effects; Cells; Cytokines; Epithelial cells; Epithelial Cells - metabolism; Forkhead protein; Gene expression; Gene Expression Regulation - drug effects; Goblet Cells - metabolism; Hepatocyte Nuclear Factor 3-beta - biosynthesis; Hepatocyte Nuclear Factor 3-gamma - biosynthesis; Humans; Hydroxyeicosatetraenoic Acids - biosynthesis; Hyperplasia; Immunoglobulins; Inflammation; Interleukin 13; Interleukin-13 - pharmacology; Kinases; Linoleic acid; Linoleic Acids - biosynthesis; Lipoxygenase; Mucin; Mucin 5AC - biosynthesis; Mucous membrane; Original Research; Phosphatidylethanolamine; Proteins; Respiratory tract; Ribonucleic acid; RNA; siRNA; Small intestine; Studies; Transfection; eicosanoid; mucus hypersecretion; asthma; 15-lipoxygenase-1; phospholipid
• ISSN: 1044-1549; 1535-4989; 1535-4989
• DOI: 10.1165/rcmb.2017-0031OC

Type 2-associated goblet cell hyperplasia and mucus hypersecretion are well known features of asthma. 15-Lipoxygenase-1 (15LO1) is induced by the type 2 cytokine IL-13 in human airway epithelial cells (HAECs) in vitro and is increased in fresh asthmatic HAECs ex vivo. 15LO1 generates a variety of products, including 15-hydroxyeicosatetraenoic acid (15-HETE), 15-HETE-phosphatidylethanolamine (15-HETE-PE), and 13-hydroxyoctadecadienoic acid (13-HODE). In this study, we investigated the 15LO1 metabolite profile at baseline and after IL-13 treatment, as well as its influence on goblet cell differentiation in HAECs. Primary HAECs obtained from bronchial brushings of asthmatic and healthy subjects were cultured under air-liquid interface culture supplemented with arachidonic acid and linoleic acid (10 μM each) and exposed to IL-13 for 7 days. Short interfering RNA transfection and 15LO1 inhibition were applied to suppress 15LO1 expression and activity. IL-13 stimulation induced expression of 15LO1 and preferentially generated 15-HETE-PE in vitro, both of which persisted after removal of IL-13. 15LO1 inhibition (by short interfering RNA and chemical inhibitor) decreased IL-13-induced forkhead box protein A3 (FOXA3) expression and enhanced FOXA2 expression. These changes were associated with reductions in both mucin 5AC and periostin. Exogenous 15-HETE-PE stimulation (alone) recapitulated IL-13-induced FOXA3, mucin 5AC, and periostin expression. The results of this study confirm the central importance of 15LO1 and its primary product, 15-HETE-PE, for epithelial cell remodeling in HAECs.