title: Regulation of MUC5AC mucin secretion and airway surface liquid metabolism by IL-1beta in human bronchial epithelia.
abstract: Mucociliary transport in the airways significantly depends on the liquid and mucin components of the airway surface liquid (ASL). The regulation of ASL water and mucin content during pathological conditions is not well understood. We hypothesized that airway epithelial mucin production and liquid transport are regulated in response to inflammatory stimuli and tested this hypothesis by investigating the effects of the pleiotropic, early-response cytokine, IL-1beta, on cultured primary human bronchial epithelial and second-passage, normal human tracheo-bronchial epithelial (NHTBE) cell cultures. Fully differentiated NHTBE cultures secreted two major airway mucins, MUC5AC and MUC5B. IL-1beta, in a dose- and time-dependent manner, increased the secretion of MUC5AC, but not MUC5B. MUC5AC mRNA levels were only transiently increased at 1 and 4 h after the start of IL-1beta treatment and returned to control levels thereafter, even though MUC5AC mucin production remained elevated for at least 72 h. Synchronous with elevated MUC5AC secretion, ASL volume increased, its percentage of solid was reduced, and the pH/[HCO(3)(-)] of the ASL was elevated. ASL volume changes reflected altered ion transport, including an upregulation of Cl(-) secretory currents (via CFTR and Ca(2+)-activated Cl(-) conductance) and an inhibition of epithelial sodium channel (ENaC)-mediated absorptive Na(+) currents. IL-1beta increased CFTR mRNA levels without affecting those for ENaC subunits. The synchronous regulation of ASL mucin and liquid metabolism triggered by IL-1beta may be an important defense mechanism of the airway epithelium to enhance mucociliary clearance during airway inflammation.
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. grayt@niehs.nih.gov
authors.forename: Thomas
authors.initials: T
authors.lastname: Gray
authors.forename: Ray
authors.initials: R
authors.lastname: Coakley
authors.forename: Andrew
authors.initials: A
authors.lastname: Hirsh
authors.forename: David
authors.initials: D
authors.lastname: Thornton
authors.forename: S
authors.initials: S
authors.lastname: Kirkham
authors.forename: Ja-Seok
authors.initials: JS
authors.lastname: Koo
authors.forename: Lauranell
authors.initials: L
authors.lastname: Burch
authors.forename: Richard
authors.initials: R
authors.lastname: Boucher
authors.forename: Paul
authors.initials: P
authors.lastname: Nettesheim
mesh_terms: D001639:Bicarbonates / Q000378:metabolism; D001980:Bronchi / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D053503:Epithelial Sodium Channels; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007375:Interleukin-1 / Q000494:pharmacology*; D055271:Mucin 5AC; D055257:Mucin-5B; D009077:Mucins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics
chemical_list: D001639:Bicarbonates; C505032:CFTR protein, human; D002712:Chlorides; D053503:Epithelial Sodium Channels; D007375:Interleukin-1; C524678:MUC5AC protein, human; C524578:MUC5B protein, human; D055271:Mucin 5AC; D055257:Mucin-5B; D009077:Mucins; D012333:RNA, Messenger; D015222:Sodium Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator