Neutrophil elastase induces mucin production by ligand-dependent epidermal growth factor receptor activation
| Autor: | Iris F. Ueki, Kazuhiro Kohri, Jay A. Nadel |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Pulmonary and Respiratory Medicine
Physiology Mucin 5AC Ligands Antibodies Cell Line Epidermal growth factor Physiology (medical) Humans Epidermal growth factor receptor Protein Precursors Mitogen-Activated Protein Kinase Kinases biology Mucin Elastase Mucins Free Radical Scavengers Cell Biology Transforming Growth Factor alpha In vitro Cell biology Enzyme Activation ErbB Receptors Biochemistry Cell culture Neutrophil elastase biology.protein Signal transduction Leukocyte Elastase Reactive Oxygen Species Peptide Hydrolases |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 283:L531-L540 |
| ISSN: | 1522-1504 1040-0605 |
| Popis: | Neutrophil products are implicated in hypersecretory airway diseases. To determine the mechanisms linking a proteolytic effect of human neutrophil elastase (HNE) and mucin overproduction, we examined the effects of HNE on MUC5AC mucin production in human airway epithelial (NCI-H292) cells. Stimulation with HNE for 5-30 min induced MUC5AC production 24 h later, which was prevented by HNE serine active site inhibitors, implicating a proteolytic effect of HNE. MUC5AC induction was preceded by epidermal growth factor receptor (EGFR) tyrosine phosphorylation and was prevented by selective EGFR tyrosine kinase inhibitors, implicating EGFR activation. HNE-induced MUC5AC production was inhibited by a neutralizing transforming growth factor-alpha (TGF-alpha, an EGFR ligand) antibody and by a neutralizing EGFR antibody but not by oxygen free radical scavengers, further implicating TGF-alpha and ligand-dependent EGFR activation in the response. HNE decreased pro-TGF-alpha in NCI-H292 cells and increased TGF-alpha in cell culture supernatant. From these results, we conclude that HNE-induced MUC5AC mucin production occurs via its proteolytic activation of an EGFR signaling cascade involving TGF-alpha. |
| Databáze: | OpenAIRE |
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