MUC18 Differentially Regulates Pro-Inflammatory and Anti-Viral Responses in Human Airway Epithelial Cells

Abstract

Objective 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. Methods 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. Results 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. Conclusions Our results for the first time demonstrate MUC18's pro-inflammatory and anti-viral function in human airway epithelial cells.

Epithelial-Mesenchymal Transition in Asthma Airway Remodeling Is Regulated by the IL-33/CD146 Axis

“…CD146 in CD4 + T cells is associated with Th17 differentiation in systemic sclerosis ( 9 ). CD146 is also associated with pulmonary infections, in which it promotes the adherence of bacteria or viruses to airway epithelial cells ( 11 – 14 ). Increased expression ofCD146 in gastric cancer leads to decreased expression of E-cadherin and increased expression of N-catenin and vimentin ( 15 ).…”

MUC18 Regulates Lung Rhinovirus Infection and Inflammation

“…A common characteristic of exacerbations of lung diseases is excessive inflammation, demonstrated by increases in neutrophils and IL-8, a chemoattractant of neutrophils. In our previous publication [ 3 ], we showed that MUC18 promotes IL-8 production in human airway epithelial cells. A study by Gern et al showed that IL-8 was rapidly induced after viral inoculation and contributed to neutrophil trafficking in the human upper airways [ 6 ].…”

“…MUC18, also referred to as CD146 or melanoma cell adhesion molecule (MCAM), is a 113 kD transmembrane glycoprotein of the immunoglobulin superfamily [ 1 , 2 ]. MUC18 is comprised of an extracellular domain, a single transmembrane domain, and a short (63 amino acids) cytoplasmic tail [ 3 ]. It is upregulated in the airways of asthmatics and patients with chronic obstructive pulmonary disease (COPD), compared to healthy controls [ 4 ].…”

“…MUC18 has been previously demonstrated to have pro-inflammatory functions in human airway epithelial cells [ 3 ] as well as mouse lungs during bacterial infections [ 5 ]. In an over-expression model of MUC18 in human airway epithelial cells with human rhinovirus (HRV) infection, MUC18 suppressed the expression of antiviral genes and promoted production of the pro-inflammatory cytokine IL-8 [ 3 ]. However, the in vivo role of MUC18 in viral infections, particularly in the context of HRV, has not yet been determined.…”