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Human Airway Trypsin-Like Protease Increases Mucin Gene Expression in Airway Epithelial Cells

Pharmacological Research Department, Teijin Institute for Bio-Medical Research, Teijin Limited, Tokyo; and Department of Nutrition, University of Tokushima School of Medicine, Tokushima City, Japan

Address correspondence to: Manabu Chokki, Pharmacological Research Department, Teijin Institute for Bio-Medical Research, Tokyo 191–8512, Japan. E-mail: m.chiyotsuki{at}teijin.co.jp

Human airway trypsin-like protease (HAT) is a serine protease found in sputum of patients with chronic airway diseases and is an agonist of protease-activated receptor-2 (PAR-2). Results from this study show that HAT treatment also enhances mucus production by the airway epithelial cell line NCI-H292 in vitro. Histologic examination showed that HAT enhances mucous glycoconjugate synthesis, whereas the PAR-2 agonist peptide (PAR-2 AP) has no such effect. HAT, but not PAR-2 AP, enhances MUC2 and MUC5AC gene expression 23-fold and 32-fold, respectively. The proteolytic activity of HAT is required to enhance MUC5AC gene expression; the addition of the inhibitors of trypsin-like protease activity of HAT, aprotinin and leupeptin, abolishes its enhancing effect. AG1478, anti-epidermal growth factor receptor (anti-EGFR)–neutralizing antibody, and anti-amphiregulin (AR)-neutralizing antibody all inhibited the stimulatory effect of HAT. Furthermore, HAT increases AR gene expression and subsequent AR protein release, whereas PAR-2 AP shows no such effects. These results indicate that HAT enhances mucin gene expression through an AR-EGFR pathway, and PAR-2 is not sufficient for or does not directly cause HAT-induced mucin gene expression. Thus, HAT might be a possible therapeutic target to prevent excessive mucus production in patients with chronic airway diseases.

Abbreviations: Alcian Blue and periodic acid-Schiff, AB-PAS • amphiregulin, AR • epidermal growth factor, EGF • epidermal growth factor receptor, EGFR • enzyme-linked immunosorbent assay, ELISA • human airway trypsin-like protease, HAT • heparin-binding EGF-like growth factor, HB-EGF • protease-activated receptor, PAR • PAR-2 agonist peptide, PAR-2 AP • heterotrimeric guanine nucleotide-binding protein, G-protein • reverse transcription–polymerase chain reaction, RT-PCR • serum-free medium, SFM • transforming growth factor-, TGF-

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