While airway inflammation is an essential host defense mechanism for inhaled bacteria, excessive and prolonged inflammation is detrimental to the host. Over the past several years, a great deal of knowledge has accrued about how airway inflammation is initiated and maintained. However, the mechanisms through which inflammation is resolved are poorly understood. MUC1 (MUC1 in human and Muc1 in nonhuman species) is a transmembrane mucin-like glycoprotein expressed on the surface of epithelial cells lining various mucosal surfaces, including the respiratory tract. We recently showed that mice deficient in Muc1 expression exhibited both enhanced airway inflammation and bacterial clearance during Pseudomonas aeruginosa (PA) airway infection, suggesting an anti-inflammatory role for Muc1 and the importance of Muc1 levels during airway bacterial infection. The anti-inflammatory activity of MUC1/Muc1 following treatment with bacterial products also was demonstrated in various in vitro studies. How the levels of MUC1/Muc1 are regulated during airway bacterial infection is unknown, but recent evidence indicates the involvement of TNF-(. In this renewal application, we will identify the mechanism by which MUC1/Muc1 is upregulated to control inflammation during airway bacterial infection. Using a lung epithelial cell line (A549 cells) as well as normal human bronchial epithelial cells fully differentiated at an air-liquid interface, we found that neutrophil elastase (NE) stimulated MUC1 production via a transcriptional mechanism. Furthermore, several lines of indirect evidence suggested that TNF-( was a critical component of the pathway by which NE induced MUC1 transcription. We hypothesize that airway inflammation is controlled by the levels of MUC1/Muc1 in the lung, which are regulated by TNF-(.
The specific aims of this application are: (1) to characterize the signaling pathway involved in NE-induced MUC1 upregulation using both genetic and immunological methods in vitro and (2) to demonstrate, using various genetically engineered mice, that airway inflammation resulting from PA infection is controlled by NE-induced TNF-( activation, which in turn upregulates MUC1 levels in the lung. Successful accomplishment of the proposed studies will shed significant insights into our current understanding of the regulation of airway inflammation and will provide pharmacological strategies to control excessive and prolonged airway inflammation during airway bacterial infection. Relevance to public: Successful completion of this project will help us better understand airway inflammation and develop pharmacological strategies toward the prevention and treatment of excessive airway inflammation associated with bacterial infection. ? ? ?
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|Kato, Kosuke; Hanss, Alec D; Zemskova, Marina A et al. (2017) Pseudomonas aeruginosa increases MUC1 expression in macrophages through the TLR4-p38 pathway. Biochem Biophys Res Commun 492:231-235|
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|Kato, Kosuke; Lillehoj, Erik P; Kim, Kwang Chul (2016) Pseudomonas aeruginosa stimulates tyrosine phosphorylation of and TLR5 association with the MUC1 cytoplasmic tail through EGFR activation. Inflamm Res 65:225-33|
|Lillehoj, Erik P; Hyun, Sang Won; Liu, Anguo et al. (2015) NEU1 Sialidase Regulates Membrane-tethered Mucin (MUC1) Ectodomain Adhesiveness for Pseudomonas aeruginosa and Decoy Receptor Release. J Biol Chem 290:18316-31|
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|Guang, Wei; Czinn, Steven J; Blanchard, Thomas G et al. (2014) Genetic regulation of MUC1 expression by Helicobacter pylori in gastric cancer cells. Biochem Biophys Res Commun 445:145-50|
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