Neutrophil elastase induces mucin production by ligand-dependent epidermal growth factor receptor activation.
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.
Kohri
Kazuhiro
K
Cardiovascular Research Institute, University of California San Francisco, 94143-0130, USA.
Ueki
Iris F
IF
Nadel
Jay A
JA
D000906:Antibodies / Q000494:pharmacology; D002460:Cell Line; D004789:Enzyme Activation / Q000502:physiology; D066246:ErbB Receptors / Q000276:immunology / Q000502:physiology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D019272:Leukocyte Elastase / Q000494:pharmacology / Q000502:physiology*; D008024:Ligands; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D055271:Mucin 5AC; D009077:Mucins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D010447:Peptide Hydrolases / Q000378:metabolism; D011498:Protein Precursors / Q000737:chemistry; D017382:Reactive Oxygen Species; D016211:Transforming Growth Factor alpha / Q000737:chemistry / Q000502:physiology
D000906:Antibodies; D016166:Free Radical Scavengers; D008024:Ligands; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D009077:Mucins; D011498:Protein Precursors; D017382:Reactive Oxygen Species; D016211:Transforming Growth Factor alpha; C052268:protransforming growth factor alpha; D066246:ErbB Receptors; D020929:Mitogen-Activated Protein Kinase Kinases; D010447:Peptide Hydrolases; D019272:Leukocyte Elastase