title: STAT6 links IL-4/IL-13 stimulation with pendrin expression in asthma and chronic obstructive pulmonary disease.
abstract: Signaling through the interleukin-4/interleukin-13 (IL-4/IL-13) receptor complex is a crucial mechanism in the development of bronchial asthma and chronic obstructive pulmonary disease (COPD). In bronchial epithelial cells, this signaling pathway leads to changes in the expression levels of several genes that are possibly involved in protection against and/or pathogenesis of these diseases. The expression of pendrin (SLC26A4), a candidate for the latter category, is upregulated by IL-4/IL-13 and leads to overproduction of mucus and increased viscosity of the airway surface liquid (ASL). Therefore, elucidating the transcriptional regulation of pendrin could aid in the development of new pharmacological leads for asthma and/or COPD therapy. Here we show that IL-4/IL-13 significantly increased human pendrin promoter activity in HEK-Blue cells but not in STAT6-deficient HEK293 Phoenix cells; that mutation of the STAT6 binding site (N(4) GAS motif) rendered the promoter insensitive to IL-4/IL-13; and that addition of the N(4) GAS motif to an IL-4/IL-13-unresponsive sequence of the human pendrin promoter conferred sensitivity to both ILs.
authors.affiliation: Institute of Pharmacology and Toxicology, Paracelsus Medical University, Salzburg, Austria. charity.nofziger@pmu.ac.at
authors.forename: C
authors.initials: C
authors.lastname: Nofziger
authors.forename: V
authors.initials: V
authors.lastname: Vezzoli
authors.forename: S
authors.initials: S
authors.lastname: Dossena
authors.forename: T
authors.initials: T
authors.lastname: Schönherr
authors.forename: J
authors.initials: J
authors.lastname: Studnicka
authors.forename: J
authors.initials: J
authors.lastname: Nofziger
authors.forename: S
authors.initials: S
authors.lastname: Vanoni
authors.forename: S
authors.initials: S
authors.lastname: Stephan
authors.forename: M E
authors.initials: ME
authors.lastname: Silva
authors.forename: G
authors.initials: G
authors.lastname: Meyer
authors.forename: M
authors.initials: M
authors.lastname: Paulmichl
mesh_terms: D001249:Asthma / Q000235:genetics / Q000503:physiopathology*; D020029:Base Pairing; D001665:Binding Sites; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D007668:Kidney; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D009093:Mucus / Q000378:metabolism; D009154:Mutation; D011401:Promoter Regions, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D012137:Respiratory System / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D000076988:Sulfate Transporters
chemical_list: D018793:Interleukin-13; D026901:Membrane Transport Proteins; C085609:SLC26A4 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D000076988:Sulfate Transporters; D015847:Interleukin-4