title: The chitinase-like protein YKL-40 is secreted by airway epithelial cells at base line and in response to compressive mechanical stress.
abstract: The chitinase-like protein YKL-40, encoded by the CHI3L1 gene, is a biomarker and functional effector of chronic inflammatory and allergic diseases. In the lung it is associated with asthma severity and reduced lung function. The cellular sources of YKL-40 in human airways and the mechanisms regulating YKL-40 expression are poorly understood. We previously showed that mechanical stress similar to that experienced during bronchoconstriction triggers epithelial cell signaling through epidermal growth factor receptor (EGFR), fibrotic mediator release, and goblet cell hyperplasia consistent with airway remodeling in asthma. We now show that well differentiated normal human bronchial epithelial cells express CHI3L1 and secrete YKL-40 under base-line culture conditions. Mechanical stress (30-cm H(2)O transcellular compressive stress) applied for 3 h induces CHI3L1 expression by ∼4-fold compared with time matched controls, resulting in increased secretion of YKL-40 by 3.6-fold 24 h after onset of the 3-h stimulus. Inhibition of EGFR or MEK1/2 (ERK kinase) significantly but incompletely attenuates mechanical stress-induced up-regulation of CHI3L1 expression in normal human bronchial epithelial cells. Direct activation of EGFR utilizing EGF-family ligands induces CHI3L1 expression. Our results reveal that human airway epithelial cells are a source of YKL-40 and demonstrate that mechanical stress potently induces CHI3L1 expression leading to increased secretion of YKL-40 protein in an EGFR and MEK1/2-dependent pathway. In the asthmatic airway mechanical stress may contribute to enhanced YKL-40 levels.
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Jin-Ah
authors.initials: JA
authors.lastname: Park
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Drazen
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Tschumperlin
mesh_terms: D054392:Adipokines; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D000071451:Chitinase-3-Like Protein 1; D066246:ErbB Receptors / Q000378:metabolism; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000378:metabolism*; D020397:Goblet Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D006967:Hypersensitivity / Q000378:metabolism; D037102:Lectins / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D013312:Stress, Physiological
chemical_list: D054392:Adipokines; D015415:Biomarkers; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D006023:Glycoproteins; D037102:Lectins; C482128:MAP2K2 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human