Human airway trypsin-like protease induces amphiregulin release through a mechanism involving protease-activated receptor-2-mediated ERK activation and TNF alpha-converting enzyme activity in airway epithelial cells.

Abstract

Human airway trypsin-like protease (HAT), a serine protease found in the sputum of patients with chronic airway diseases, is an agonist of protease-activated receptor-2 (PAR-2). Previous results have shown that HAT enhances the release of amphiregulin (AR); further, it causes MUC5AC gene expression through the AR-epidermal growth factor receptor pathway in the airway epithelial cell line NCI-H292. In this study, the mechanisms by which HAT-induced AR release can occur were investigated. HAT-induced AR gene expression was mediated by extracellular signal-regulated kinase (ERK) pathway, as pretreatment of cells with ERK pathway inhibitor eliminated the effect of HAT on AR mRNA. Both HAT and PAR-2 agonist peptide (PAR-2 AP) induced ERK phosphorylation; further, desensitization of PAR-2 with a brief exposure of cells to PAR-2 AP resulted in inhibition of HAT-induced ERK phosphorylation, suggesting that HAT activates ERK through PAR-2. Moreover, PAR-2 AP induced AR gene expression subsequent to protein production in the cellular fraction through the ERK pathway indicating that PAR-2-mediated activation of ERK is essential for HAT-induced AR production. However, in contrast to HAT, PAR-2 AP could not cause AR release into extracellular space; it appears that activation of PAR-2 is not sufficient for HAT-induced AR release. Finally, HAT-induced AR release was eliminated by blockade of tumour necrosis factor alpha-converting enzyme (TACE) by the TAPI-1 and RNA interference, suggesting that TACE activity is necessary for HAT-induced AR release. These observations show that HAT induces AR production through the PAR-2 mediated ERK pathway, and then causes AR release by a TACE-dependent mechanism.

• Authors: Manabu Chokki, Hiroshi Eguchi, Ichiro Hamamura, Hiroaki Mitsuhashi, Takashi Kamimura
• Journal: The FEBS journal (FEBS J) Vol. 272 Issue 24 Pg. 6387-99 (Dec 2005) ISSN: 1742-464X [Print] England
• PMID: 16336275 (Publication Type: Journal Article)

Chemical References

• AREG protein, human
• Amphiregulin
• EGF Family of Proteins
• Glycoproteins
• Intercellular Signaling Peptides and Proteins
• Receptor, PAR-2
• Extracellular Signal-Regulated MAP Kinases
• Serine Endopeptidases
• human airway trypsin-like protease
• ADAM Proteins
• ADAM17 Protein
• ADAM17 protein, human

Topics

• ADAM Proteins (metabolism)
• ADAM17 Protein
• Amphiregulin
• Cell Line
• EGF Family of Proteins
• Epithelial Cells (metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Glycoproteins (metabolism)
• Humans
• Intercellular Signaling Peptides and Proteins (metabolism)
• Phosphorylation
• Receptor, PAR-2 (agonists, metabolism)
• Respiratory System (cytology)
• Serine Endopeptidases (physiology)
• Signal Transduction
• Transfection