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* Laboratory of Molecular Genetics, Istituto Giannina Gaslini, Genova, Italy;
Advanced Biotechnology Center, Genova, Italy;
Unita Operativa Medical Genetics, Policlinico Orsola-Malpighi, Bologna, Italy;
Functional Genomics, National Cancer Research Institute, Genova, Italy; and
¶ Laboratorio Centrale di Analisi, Istituto Giannina Gaslini, Genova, Italy
SCN– (thiocyanate) is an important physiological anion involved in innate defense of mucosal surfaces. SCN– is oxidized by H2O2, a reaction catalyzed by lactoperoxidase, to produce OSCN– (hypothiocyanite), a molecule with antimicrobial activity. Given the importance of the availability of SCN– in the airway surface fluid, we studied transepithelial SCN– transport in the human bronchial epithelium. We found evidence for at least three mechanisms for basolateral to apical SCN– flux. cAMP and Ca2+ regulatory pathways controlled SCN– transport through cystic fibrosis transmembrane conductance regulator and Ca2+-activated Cl– channels, respectively, the latter mechanism being significantly increased by treatment with IL-4. Stimulation with IL-4 also induced the strong up-regulation of an electroneutral SCN–/Cl– exchange. Global gene expression analysis with microarrays and functional studies indicated pendrin (SLC26A4) as the protein responsible for this SCN– transport. Measurements of H2O2 production at the apical surface of bronchial cells indicated that the extent of SCN– transport is important to modulate the conversion of this oxidant molecule by the lactoperoxidase system. Our studies indicate that the human bronchial epithelium expresses various SCN– transport mechanisms under resting and stimulated conditions. Defects in SCN– transport in the airways may be responsible for susceptibility to infections and/or decreased ability to scavenge oxidants.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from Telethon-Italy (GGP05103), the Cystic Fibrosis Foundation Therapeutics, Comitato Interministeriale Programmazione Economica Regione Liguria (Biofarma 2), and the National Institutes of Health (P30 DK072517).
2 Address correspondence and reprint requests to Dr. Luis J. V. Galietta, Laboratorio di Genetica Molecolare, L.go Gerolamo Gaslini 5, 16147 Genova, Italy. E-mail address: galietta{at}unige.it
3 Abbreviations used in this paper: CF, cystic fibrosis; FRT, Fischer rat thyroid; siRNA, short-interfering RNA; YFP, yellow fluorescent protein; CFTR, cystic fibrosis transmembrane conductance regulator; PDS, pendrin.
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