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(American Journal of Pathology. 2006;169:2031-2041.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060146

MUC5AC, a Gel-Forming Mucin Accumulating in Gallstone Disease, Is Overproduced via an Epidermal Growth Factor Receptor Pathway in the Human Gallbladder

Laetitia Finzi*{dagger}, Véronique Barbu*{dagger}, Pierre-Regis Burgel{ddagger}, Martine Mergey*{dagger}, Kimberly S. Kirkwood§, Elizabeth C. Wick§, Jean-Yves Scoazec, Frédérique Peschaud||, François Paye*{dagger}**, Jay A. Nadel{dagger}{dagger} and Chantal Housset*{dagger}{ddagger}{ddagger}

From INSERM,* Unité Mixte de Recherches U680, Paris, France; Faculté de Médecine,{dagger} Université Pierre et Marie Curie (Paris 6), Paris, France; Assistance Publique-Hopitaux de Paris (AP-HP),{ddagger} Service de Pneumologie, Hôpital Cochin, Unité Propre de Recherche et de l’Enseignement Supérieur, Equipe d’Accueil 2511, Paris, France; the Department of Surgery§ and the Cardiovascular Research Institute and Departments of Medicine and Physiology,{dagger}{dagger} University of California, San Francisco, California; Service d’Anatomie Pathologique, Hôpital Edouard Herriot, Lyon, France; AP-HP,|| Service de Chirurgie Digestive, Hôpital Ambroise Paré, Boulogne, France; AP-HP,** Service de Chirurgie Digestive, Hôpital Saint-Antoine, Paris, France; and AP-HP,{ddagger}{ddagger} Service de Biochimie-Hormonologie, Hôpital Tenon, Paris, France

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.






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Copyright © 2006 by the American Society for Investigative Pathology.