Human airway trypsin-like protease increases mucin gene expression in airway epithelial cells.
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.
D066258:Amphiregulin; D007611:Aprotinin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066255:EGF Family of Proteins; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D006001:Glycoconjugates / Q000378:metabolism; D006023:Glycoproteins / Q000187:drug effects / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007976:Leupeptins / Q000494:pharmacology; D055271:Mucin 5AC; D055262:Mucin-2; D009077:Mucins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D011799:Quinazolines; D044464:Receptor, PAR-2 / Q000819:agonists / Q000235:genetics; D020545:Respiratory Mucosa / Q000378:metabolism; D012137:Respiratory System / Q000166:cytology / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology
C587848:AREG protein, human; D066258:Amphiregulin; D066255:EGF Family of Proteins; D006001:Glycoconjugates; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D007976:Leupeptins; C524625:MUC2 protein, human; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D055262:Mucin-2; D009077:Mucins; D011480:Protease Inhibitors; D011799:Quinazolines; D044464:Receptor, PAR-2; D020032:Tyrphostins; C101044:RTKI cpd; D007611:Aprotinin; D066246:ErbB Receptors; D012697:Serine Endopeptidases; C112256:human airway trypsin-like protease; C032854:leupeptin