title: Induction of mucin and MUC5AC expression by the protease activity of Aspergillus fumigatus in airway epithelial cells.
abstract: Allergic bronchopulmonary mycosis, characterized by excessive mucus secretion, airflow limitation, bronchiectasis, and peripheral blood eosinophilia, is predominantly caused by a fungal pathogen, Aspergillus fumigatus. Using DNA microarray analysis of NCI-H292 cells, a human bronchial epithelial cell line, stimulated with fungal extracts from A. fumigatus, Alternaria alternata, or Penicillium notatum, we identified a mucin-related MUC5AC as one of the genes, the expression of which was selectively induced by A. fumigatus. Quantitative RT-PCR, ELISA, and histochemical analyses confirmed an induction of mucin and MUC5AC expression by A. fumigatus extracts or the culture supernatant of live microorganisms in NCI-H292 cells and primary cultures of airway epithelial cells. The expression of MUC5AC induced by A. fumigatus extracts diminished in the presence of neutralizing Abs or of inhibitors of the epidermal growth factor receptor or its ligand, TGF-α. We also found that A. fumigatus extracts activated the TNF-α-converting enzyme (TACE), critical for the cleavage of membrane-bound pro-TGF-α, and its inhibition with low-molecular weight inhibitors or small interfering RNA suppressed the expression of MUC5AC. The protease activity of A. fumigatus extracts was greater than that of other fungal extracts, and treatment with a serine protease inhibitor, but not with a cysteine protease inhibitor, eliminated its ability to activate TACE or induce the expression of MUC5AC mRNA in NCI-H292. In conclusion, the prominent serine protease activity of A. fumigatus, which caused the overproduction of mucus by the bronchial epithelium via the activation of the TACE/TGF-α/epidermal growth factor receptor pathway, may be a pathogenetic mechanism of allergic bronchopulmonary mycosis.
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Oguma
authors.forename: Koichiro
authors.initials: K
authors.lastname: Asano
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Tomomatsu
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kodama
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukunaga
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Shiomi
authors.forename: Nao
authors.initials: N
authors.lastname: Ohmori
authors.forename: Soichiro
authors.initials: S
authors.lastname: Ueda
authors.forename: Takahisa
authors.initials: T
authors.lastname: Takihara
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Shiraishi
authors.forename: Koichi
authors.initials: K
authors.lastname: Sayama
authors.forename: Shizuko
authors.initials: S
authors.lastname: Kagawa
authors.forename: Yukikazu
authors.initials: Y
authors.lastname: Natori
authors.forename: Craig M
authors.initials: CM
authors.lastname: Lilly
authors.forename: Kazuo
authors.initials: K
authors.lastname: Satoh
authors.forename: Koichi
authors.initials: K
authors.lastname: Makimura
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Ishizaka
mesh_terms: D051722:ADAM Proteins / Q000502:physiology; D000072198:ADAM17 Protein; D000818:Animals; D001232:Aspergillus fumigatus / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D066246:ErbB Receptors / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D015966:Gene Expression Regulation, Fungal / Q000276:immunology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D055271:Mucin 5AC / Q000096:biosynthesis* / Q000235:genetics; D009077:Mucins / Q000096:biosynthesis* / Q000235:genetics; D020545:Respiratory Mucosa / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology*; D057057:Serine Proteases / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000502:physiology
chemical_list: C524678:MUC5AC protein, human; D055271:Mucin 5AC; D009077:Mucins; D016211:Transforming Growth Factor alpha; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D057057:Serine Proteases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse