Abstract
MUC18 or CD146, a transmembrane glycoprotein, is mainly expressed by endothelial cells and smooth muscle cells where it serves as a cell-cell adhesion molecule. We have found MUC18 up-regulation in airway epithelial cells of patients with asthma and chronic obstructive pulmonary disease (COPD). However, the function of MUC18 in airway epithelial cells remains unclear. In the present study, we tested the hypothesis that MUC18 exerts a pro-inflammatory function during stimulation with a viral mimic polyI:C or human rhinovirus infection. Normal human primary airway epithelial cells were transduced with lentivirus encoding MUC18 cDNA to over-express MUC18 or with GFP (control), and treated with polyI:C or HRV for detection of pro-inflammatory cytokine IL-8 and anti-viral gene IFN-β. Additionally, we performed cell culture of human lung epithelial cell line NCIH292 cells to determine the mechanisms of MUC18 function. We found that MUC18 over-expression promoted IL-8 production, while it inhibited IFN-β expression following polyI:C stimulation or HRV infection. Increased phosphorylation of MUC18 serines was observed in MUC18 over-expressing cells. Reduction of MUC18 serine phosphorylation by inhibiting ERK activity was associated with less production of IL-8 following polyI:C stimulation. Our results for the first time demonstrate MUC18's pro-inflammatory and anti-viral function in human airway epithelial cells.
Highlights
Excessive inflammation is a common feature during exacerbations of various lung diseases, including asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis
MUC18 is critical to bacteria-induced lung inflammation, which is in part through activation of NFκB signaling [13,14]
We examined the role of MUC18 serine phosphorylation and activation of ERK, a major component of the mitogen-activated protein kinases (MAPK) signaling pathway, in MUC18-mediated effects
Summary
Excessive inflammation is a common feature during exacerbations of various lung diseases, including asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. The mechanisms underlying excessive lung inflammation of lung disease exacerbations remain unclear. MUC18 overexpression was initially identified in human malignant melanoma cells and was thought to promote tumor metastasis [10,11,12]. MUC18 regulation and function in inflammatory lung diseases such as asthma or COPD are poorly understood. Our recent publications [13,14] demonstrated MUC18 upregulation in airway epithelial cells of asthmatics and COPD patients. Whether MUC18 promotes inflammatory responses to Tolllike receptor (TLR) ligands mimicking viral infection or viruses has not been investigated. The molecular mechanisms by which MUC18 promotes the inflammatory response are unclear
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