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.
Highlights
Cigarette smoke (CS) is well known for its association with many respiratory diseases including asthma, emphysema and lung cancer [1,2]
Among all the cytokines and chemokines, robustly increased IL-8 levels are found in sputum from patients with chronic obstructive pulmonary diseases (COPD) [8,30] and at the time of exacerbation [31,32]
The Wnt pathway components were increased, such as Dvl2. bcatenin translocated from cell surface to cytosol and nucleus, subsequently triggered the release of IL-8
Summary
Cigarette smoke (CS) is well known for its association with many respiratory diseases including asthma, emphysema and lung cancer [1,2]. In bronchoalveolar lavage fluids (BALF) from smokers, elevated neutrophils, eosinophils and macrophages are found [3,4]. The accumulation of these inflammatory cells is thought to occur after the release of chemotactic factors from lung epithelial cells in response to CS [5]. Infiltration of inflammatory cells is associated the consequent lung injury and remodeling involved in chronic obstructive pulmonary diseases (COPD) [5]. High concentrations of IL-8 have been detected from the induced sputum or BALF obtained from patients with a variety of respiratory conditions, including many CS related diseases, such as chronic obstructive pulmonary diseases (COPD) and chronic airway disease [7,8]
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