Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease.
An unresolved question in cystic fibrosis (CF) research is how mutations of the CF transmembrane conductance regulator, a Cl ion channel, cause airway mucus obstruction leading to fatal lung disease. Recent evidence has linked the CF transmembrane conductance regulator mutation to the onset and persistence of Pseudomonas aeruginosa infection in the airways, and here we provide evidence directly linking P. aeruginosa infection to mucus overproduction. We show that P. aeruginosa lipopolysaccharide profoundly upregulates transcription of the mucin gene MUC 2 in epithelial cells via inducible enhancer elements and that this effect is blocked by the tyrosine kinase inhibitors genistein and tyr-phostin AG 126. These findings improve our understanding of CF pathogenesis and suggest that the attenuation of mucin production by lipopolysaccharide antagonists and tyrosine kinase inhibitors could reduce morbidity and mortality in this disease.
Li
J D
JD
Department of Anatomy, Cardiovascular Research Institute, University of California, San Francisco 94143, USA.
Dohrman
A F
AF
Gallup
M
M
Miyata
S
S
Gum
J R
JR
Kim
Y S
YS
Nadel
J A
JA
Prince
A
A
Basbaum
C B
CB
D001597:Benzylidene Compounds / Q000494:pharmacology; D001980:Bronchi / Q000378:metabolism; D002460:Cell Line; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000382:microbiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008969:Molecular Sequence Data; D055262:Mucin-2; D009077:Mucins / Q000235:genetics*; D009570:Nitriles / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011550:Pseudomonas aeruginosa / Q000737:chemistry / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D015533:Transcriptional Activation / Q000187:drug effects; D020032:Tyrphostins
D001597:Benzylidene Compounds; C505032:CFTR protein, human; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C524625:MUC2 protein, human; D055262:Mucin-2; D009077:Mucins; D009570:Nitriles; D012333:RNA, Messenger; D020032:Tyrphostins; C069028:AG 127; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D011505:Protein-Tyrosine Kinases