title: Cigarette smoke induces growth differentiation factor 15 production in human lung epithelial cells: implication in mucin over-expression.
abstract: Excessive mucus is a hallmark of chronic obstructive pulmonary disease (COPD). There is an emerging interest in the role of TGF-β signaling in the initiation and progression of COPD. Growth differentiation factor 15 (GDF15) is a divergent member of TGF-β superfamily. However, whether cigarette smoke induces airway epithelial GDF15 production and its functions in the airways have not been revealed. Therefore, we first analyzed GDF15 protein expression in airway epithelium of human COPD smokers versus normal non-smokers. We then examined the regulation and function of GDF15 in human airway epithelial cells in response to cigarette smoke exposure. We found increased GDF15 protein expression in airway epithelium (mainly in ciliated cells) of human COPD smokers compared with normal non-smokers. Furthermore, cigarette smoke exposure consistently up-regulated GDF15 expression in human airway epithelial cells. Moreover, GDF15 was shown to play a critical role in cigarette smoke-induced airway epithelial MUC5AC expression. Lastly, activation of phosphoinositide 3-kinase (PI3K) pathway was largely responsible for GDF15-induced airway epithelial MUC5AC expression. Our findings indicate that human airway epithelial cells can produce GDF15 during cigarette smoke exposure, which subsequently activates PI3K pathway to promote mucin (e.g. MUC5AC) expression. This highlights a novel role of GDF15 in regulating airway mucosal immunity (e.g. mucin) in cigarette smoke-exposed lungs.
authors.affiliation: Department of Medicine, National Jewish Health and the University of Colorado Denver, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wu
authors.forename: Di
authors.initials: D
authors.lastname: Jiang
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Chu
mesh_terms: D002478:Cells, Cultured; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D055436:Growth Differentiation Factor 15 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018928:Immunity, Mucosal; D008168:Lung / Q000276:immunology*; D055271:Mucin 5AC / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D012907:Smoking / Q000009:adverse effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D055436:Growth Differentiation Factor 15; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D016212:Transforming Growth Factor beta; D019869:Phosphatidylinositol 3-Kinases