title: Allergen-induced IL-9 directly stimulates mucin transcription in respiratory epithelial cells.
abstract: A hallmark of asthma is mucin overproduction, a condition that contributes to airway obstruction. The events responsible for mucin overproduction are not known but are thought to be associated with mediators of chronic inflammation. Others have shown that T-helper 2 (Th2) lymphocytes are required for mucous cell metaplasia, which then leads to mucin overproduction in animal models of allergy. We hypothesized that Th2 cell mediators are present in asthmatic airway fluid and directly stimulate mucin synthesis in airway epithelial cells. Results in cultured airway epithelial cells showed that samples of asthmatic fluid stimulated mucin (MUC5AC) synthesis severalfold more potently than non-asthmatic fluid. Consistent with this, lavage fluid from the airways of allergen-challenged dogs stimulated mucin synthesis severalfold more potently than that from non-allergen-challenged dogs. Fractionation of dog samples revealed 2 active fractions at <10 kDa and 30-100 kDa. Th2 cytokines in these molecular weight ranges are IL-9 (36 kDa), IL-5 (56 kDa), and IL-13 (10 kDa). Antibody blockade of ligand-receptor interaction for IL-9 (but not IL-5 or IL-13) inhibited mucin stimulation by dog airway fluid. Furthermore, recombinant IL-9, but not IL-5 or IL-13, stimulated mucin synthesis. These results indicate that IL-9 may account for as much as 50-60% of the mucin-stimulating activity of lung fluids in allergic airway disease.
authors.affiliation: Department of Anatomy and Cardiovascular Research Institute, School of Medicine, University of California-San Francisco, San Francisco, California 94143, USA. longphrm@bms.com
authors.forename: M
authors.initials: M
authors.lastname: Longphre
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Gallup
authors.forename: E
authors.initials: E
authors.lastname: Drori
authors.forename: C L
authors.initials: CL
authors.lastname: Ordoñez
authors.forename: T
authors.initials: T
authors.lastname: Redman
authors.forename: S
authors.initials: S
authors.lastname: Wenzel
authors.forename: D E
authors.initials: DE
authors.lastname: Bice
authors.forename: J V
authors.initials: JV
authors.lastname: Fahy
authors.forename: C
authors.initials: C
authors.lastname: Basbaum
mesh_terms: D000328:Adult; D000485:Allergens; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D001980:Bronchi / Q000166:cytology / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000032:analysis; D004285:Dogs; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016906:Interleukin-9 / Q000235:genetics / Q000502:physiology*; D007378:Interleukins / Q000032:analysis / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055271:Mucin 5AC; D009077:Mucins / Q000096:biosynthesis / Q000235:genetics*; D018123:Receptors, Interleukin / Q000032:analysis / Q000235:genetics; D053651:Receptors, Interleukin-9; D011994:Recombinant Proteins / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology*; D014132:Trachea / Q000166:cytology / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000485:Allergens; D016207:Cytokines; C508045:IL9R protein, human; D016906:Interleukin-9; D007378:Interleukins; C524678:MUC5AC protein, human; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D009077:Mucins; D018123:Receptors, Interleukin; D053651:Receptors, Interleukin-9; D011994:Recombinant Proteins