title: CCN1 secretion induced by cigarette smoking extracts augments IL-8 release from bronchial epithelial cells.
abstract: Inflammation involves in many cigarette smoke (CS) related diseases including the chronic obstructive pulmonary disease (COPD). Lung epithelial cell released IL-8 plays a crucial role in CS induced lung inflammation. CS and cigarette smoke extracts (CSE) both induce IL-8 secretion and subsequently, IL-8 recruits inflammatory cells into the lung parenchyma. However, the molecular and cellular mechanisms by which CSE triggers IL-8 release remain not completely understood. In this study, we identified a novel extracellular matrix (ECM) molecule, CCN1, which mediated CSE induced IL-8 secretion by lung epithelial cells. We first found that CS and CSE up-regulated CCN1 expression and secretion in lung epithelial cells in vivo and in vitro. CSE up-regulated CCN1 via induction of reactive oxygen spices (ROS) and endoplasmic reticulum (ER) stress. p38 MAPK and JNK activation were also found to mediate the signal pathways in CSE induced CCN1. CCN1 was secreted into ECM via Golgi and membrane channel receptor aquaporin4. After CSE exposure, elevated ECM CCN1 functioned via an autocrine or paracrine manner. Importantly, CCN1 activated Wnt pathway receptor LRP6, subsequently stimulated Wnt pathway component Dvl2 and triggered beta-catenin translocation from cell membrane to cytosol and nucleus. Treatment of Wnt pathway inhibitor suppressed CCN1 induced IL-8 secretion from lung epithelial cells. Taken together, CSE increased CCN1 expression and secretion in lung epithelial cells via induction of ROS and ER stress. Increased ECM CCN1 resulted in augmented IL-8 release through the activation of Wnt pathway.
authors.affiliation: Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Hyung-Geun
authors.initials: HG
authors.lastname: Moon
authors.forename: Yijie
authors.initials: Y
authors.lastname: Zheng
authors.forename: Chang Hyeok
authors.initials: CH
authors.lastname: An
authors.forename: Yoon-Keun
authors.initials: YK
authors.lastname: Kim
authors.forename: Yang
authors.initials: Y
authors.lastname: Jin
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D010936:Plant Extracts / Q000009:adverse effects*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000737:chemistry*; D060449:Wnt Signaling Pathway
chemical_list: D051401:Aquaporin 4; D055515:Cysteine-Rich Protein 61; D016209:Interleukin-8; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008565:Membrane Proteins; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D012906:Smoke; C403982:ERN2 protein, human; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D004722:Endoribonucleases