CFTR antisense phosphorothioate oligodeoxynucleotides (S-ODns) induce tracheo-bronchial mucin (TBM) mRNA expression in human airway mucosa.
Mucus hypersecretion is a critical component of cystic fibrosis (CF) pathogenesis. The effects of dysfunction of the cystic fibrosis transmembrane regulator (CFTR) on mucin expression were examined using the tracheo-bronchial mucin (TBM) gene as an indicator. TBM mRNA expression was assessed in a human bronchial epithelial cell line (HBE1) and human nasal mucosal explants in vitro. Antisense phosphorothioate oligodeoxynucleotides (S-ODN) to TBM suppressed baseline expression of TBM mRNA in both systems, but had no effect on glyceraldehyde phosphate dehydrogenase mRNA (GAPDH) expression. Sense and missense (multiple scrambled control oligonucleotides) S-ODNs had no effect. 8Br-cAMP and PGE1 significantly elevated TBM mRNA expression. These increases were also specifically inhibited by the antisense S-ODNs. In order to induce a CF-like state, S-ODN to CFTR were added to explants. Antisense CFTR S-ODNs were anticipated to reduce the expression of cellular CFTR protein, and the level of CFTR function. Antisense, but not sense or missense, CFTR S-ODN significantly increased TBM mRNA expression. These data suggest that mucin hypersecretion in CF may be a direct consequence of CFTR dysfunction; the specific mechanism through which this effect is mediated is not known.
Verma
M
M
Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20007, USA.
Baraniuk
J
J
Blass
C
C
Ali
M
M
Yuta
A
A
Biedlningmaier
J
J
Davidson
E A
EA
D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D009297:Nasal Mucosa / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics
C505032:CFTR protein, human; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator