MUC5AC, a gel-forming mucin accumulating in gallstone disease, is overproduced via an epidermal growth factor receptor pathway in the human gallbladder.
Despite evidence that mucin overproduction is critical in the pathogenesis of gallstones, the mechanisms triggering mucin production in gallstone disease are unknown. Here, we tested the potential implication of an inflammation-dependent epidermal growth factor receptor (EGF-R) pathway in the regulation of gallbladder mucin synthesis. In gallbladder tissue sections from subjects with cholesterol gallstones, mucus accumulation was associated with neutrophil infiltration and with increased expressions of EGF-R and of tumor necrosis factor-alpha (TNF-alpha). In primary cultures of human gallbladder epithelial cells, TNF-alpha induced EGF-R overexpression. In the presence of TNF-alpha, EGF-R ligands (either EGF or transforming growth factor-alpha) caused significant increases in MUC5AC mRNA and protein production, whereas expression of the other gallbladder mucins MUC1, MUC3, and MUC5B was unchanged. In addition, on gallbladder tissue sections from subjects with gallstones, increased MUC5AC immunoreactivity was detected in the epithelium and within mucus gel in the lumen. Studies in primary cultures demonstrated that MUC5AC up-regulation induced by the combination of TNF-alpha with EGF-R ligands was completely blunted by inhibitors of EGF-R tyrosine kinase and mitogen-activated protein/extracellular signal-related kinase kinase. In conclusion, an inflammation-dependent EGF-R cascade causes overproduction of the gel-forming mucin MUC5AC, which accumulates in cholesterol gallstone disease. The ability to interrupt this cascade is of potential interest in the prevention of cholesterol gallstones.
Finzi
Laetitia
L
INSERM U680, Faculté de Médecine Pierre et Marie Curie (Université Pierre et Marie Curie-Paris 6), Site Saint-Antoine, 27 rue Chaligny, 75571 Paris cedex 12, France.
Barbu
Véronique
V
Burgel
Pierre-Regis
PR
Mergey
Martine
M
Kirkwood
Kimberly S
KS
Wick
Elizabeth C
EC
Scoazec
Jean-Yves
JY
Peschaud
Frédérique
F
Paye
François
F
Nadel
Jay A
JA
Housset
Chantal
C
D002478:Cells, Cultured; D002769:Cholelithiasis / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005704:Gallbladder / Q000378:metabolism*; D042882:Gallstones / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D055271:Mucin 5AC; D009077:Mucins / Q000378:metabolism*; D020556:Neutrophil Infiltration; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology; D015854:Up-Regulation
C524678:MUC5AC protein, human; D055271:Mucin 5AC; D009077:Mucins; D014409:Tumor Necrosis Factor-alpha; D066246:ErbB Receptors