Cigarette smoke induces mucin hypersecretion and inflammatory response through the p66shc adaptor protein-mediated mechanism in human bronchial epithelial cells. (January 2016)

• Record Type: Journal Article
• Authors: Yang, J.; Yu, H.M.; Zhou, X.D.; Huang, H.P.; Han, Zh.; Kolosov, V.P.; Perelman, J.M.
• Is Part Of: Molecular immunology. Volume 69(2016:Jan.)
• Page Start: 86
• Page End: 98
• Publication Date: 2016-01
• Subjects: p66Shc -- Mitochondria -- ROS -- NF-κB -- Inflammation -- MUC5AC; Immunochemistry -- Periodicals; Molecular biology -- Periodicals; Immunochemistry -- Periodicals; Allergy and Immunology -- Periodicals; Molecular Biology -- Periodicals; Immunochimie -- Périodiques; Biologie moléculaire -- Périodiques; Immunochemistry; Molecular biology; Periodicals; Electronic journals; 571.96
• DOI: 10.1016/j.molimm.2015.11.002
• Languages: English
• ISSNs: 0161-5890

Abstract

Highlights: p66Shc adaptor protein is a newly recognized mediator of mitochondrial dysfunction. Expression of p66Shc was significantly increased in human airway epithelial cells with CSE exposure. The high expression of p66Shc induced excess of intracellular ROS production and mitochondria dysfunction. Excessive ROS triggers the inflammatory response and mucus hypersecretion in part by activating NF-κB signaling and inhibiting FoxO3a activity. Manipulating p66Shc might offer a new therapeutic modality with which to treat chronic inflammatory airway diseases. Abstract: The p66Shc adaptor protein is a newly recognized mediator of mitochondrial dysfunction and might play a role in cigarette smoke (CS)-induced airway epithelial cell injury. CS can induce an excessive amount of reactive oxygen species (ROS) generation, which can cause mitochondrial depolarization and injury through the oxidative stress-mediated Serine36 phosphorylation of p66Shc. The excessive production of ROS can trigger an inflammatory response and mucin hypersecretion by enhancing the transcriptional activity of pro-inflammatory cytokines and mucin genes. Therefore, we speculate that p66Shc plays an essential role in airway epithelial cell injury and the process of mucin generation in CS-induced chronic inflammatory airway diseases. Our present study focuses on the role of p66Shc in ROS generation, and on the resulting mitochondrial dysfunction, inflammatory response and mucus hypersecretion in CS-stimulated human bronchial epithelial cells (16HBE). We found that CS disturbed the mitochondrial function by increasing the level of phosphorylated p66Shc in these cells and that the effects were significantly reduced by silencing p66Shc. Conversely, the ectopic overexpression of wild-type p66Shc enhanced these effects. We also found that high levels of ROS inhibited FOXO3a transcriptional activity, which led to NF-κB activation. Subsequently, activated NF-κB promoted pro-inflammatory cytokine production and mucin hypersecretion. Thus, manipulating p66Shc might offer a new therapeutic modality with which to treat chronic inflammatory airway diseases.