MUC5AC, a gel-forming mucin accumulating in gallstone disease, is overproduced via an epidermal growth factor receptor pathway in the human gallbladder

Laetitia Finzi, Véronique Barbu, Pierre Regis Burgel, Martine Mergey, Kimberly S. Kirkwood, Elizabeth C. Wick, Jean Yves Scoazec, Frédérique Peschaud, François Paye, Jay A. Nadel, Chantal Housset

Research output: Contribution to journalArticle

Abstract

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-α (TNF-α). In primary cultures of human gallbladder epithelial cells, TNF-α induced EGF-R overexpression. In the presence of TNF-α, EGF-R ligands (either EGF or transforming growth factor-α) 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-α 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.

Original languageEnglish (US)
Pages (from-to)2031-2041
Number of pages11
JournalAmerican Journal of Pathology
Volume169
Issue number6
DOIs
StatePublished - Dec 2006
Externally publishedYes

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Gallstones
Mucins
Gallbladder
Epidermal Growth Factor Receptor
Gels
Tumor Necrosis Factor-alpha
Cholesterol
Mucus
Phosphotransferases
Ligands
Inflammation
Neutrophil Infiltration
Transforming Growth Factors
Mitogens
Epidermal Growth Factor
Protein-Tyrosine Kinases
Proteins
Up-Regulation
Epithelium
Epithelial Cells

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

MUC5AC, a gel-forming mucin accumulating in gallstone disease, is overproduced via an epidermal growth factor receptor pathway in the human gallbladder. / Finzi, Laetitia; Barbu, Véronique; Burgel, Pierre Regis; Mergey, Martine; Kirkwood, Kimberly S.; Wick, Elizabeth C.; Scoazec, Jean Yves; Peschaud, Frédérique; Paye, François; Nadel, Jay A.; Housset, Chantal.

In: American Journal of Pathology, Vol. 169, No. 6, 12.2006, p. 2031-2041.

Research output: Contribution to journalArticle

Finzi, L, Barbu, V, Burgel, PR, Mergey, M, Kirkwood, KS, Wick, EC, Scoazec, JY, Peschaud, F, Paye, F, Nadel, JA & Housset, C 2006, 'MUC5AC, a gel-forming mucin accumulating in gallstone disease, is overproduced via an epidermal growth factor receptor pathway in the human gallbladder', American Journal of Pathology, vol. 169, no. 6, pp. 2031-2041. https://doi.org/10.2353/ajpath.2006.060146
Finzi, Laetitia ; Barbu, Véronique ; Burgel, Pierre Regis ; Mergey, Martine ; Kirkwood, Kimberly S. ; Wick, Elizabeth C. ; Scoazec, Jean Yves ; Peschaud, Frédérique ; Paye, François ; Nadel, Jay A. ; Housset, Chantal. / MUC5AC, a gel-forming mucin accumulating in gallstone disease, is overproduced via an epidermal growth factor receptor pathway in the human gallbladder. In: American Journal of Pathology. 2006 ; Vol. 169, No. 6. pp. 2031-2041.
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AU - Finzi, Laetitia

AU - Barbu, Véronique

AU - Burgel, Pierre Regis

AU - Mergey, Martine

AU - Kirkwood, Kimberly S.

AU - Wick, Elizabeth C.

AU - Scoazec, Jean Yves

AU - Peschaud, Frédérique

AU - Paye, François

AU - Nadel, Jay A.

AU - Housset, Chantal

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