title: Pancreatic regeneration in chronic pancreatitis requires activation of the notch signaling pathway.
abstract: Chronic pancreatitis as an inflammatory process characterized by morphological changes, pancreatic dysfunction, and pain. During pancreatic injury and repair the Notch signaling pathway is reinstated. The current study analyzed this pathway in chronic pancreatitis and characterized its influence on fibrogenesis. Real-time quantitative PCR and immunohistochemistry were used for expression studies. Notch activation was determined by a specific luciferase-HES-1-reporter gene constructs. Cells were stimulated with alcohol, glucose, bile acids, and steroids. Notch-2, -3, and -4 mRNA, were overexpressed in chronic pancreatitis specimens. The ligands Jagged-1, -2, and Delta-1 were highly overexpressed. Jagged-1 and Notch receptors were observed in nerves, regenerating exocrine cells, and endocrine cells. Delta staining was present in ductal but not in acinus cells and not in nerves. Activation of Notch signaling was detectable upon cell stimulation with glucose, steroids, and bile acids. High glucose levels were further associated with increased collagen-I production. The Notch pathway is reactivated during chronic pancreatitis. Among the stimuli activating the Notch pathway are steroids, high glucose levels, and bile acids. These findings suggest a possible role of the Notch pathway during pancreatic regeneration since Jagged-1 inhibits inducible collagen-1 production, suggesting a new mechanism of tissue repair in this disease.
authors.affiliation: Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Yun
authors.initials: Y
authors.lastname: Su
authors.forename: Peter
authors.initials: P
authors.lastname: Büchler
authors.forename: Amiq
authors.initials: A
authors.lastname: Gazdhar
authors.forename: Nathalia
authors.initials: N
authors.lastname: Giese
authors.forename: Howard A
authors.initials: HA
authors.lastname: Reber
authors.forename: Oscar J
authors.initials: OJ
authors.lastname: Hines
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008024:Ligands; D049410:Luciferases, Renilla; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D010179:Pancreas / Q000502:physiology*; D019512:Pancreatitis, Alcoholic / Q000378:metabolism / Q000473:pathology*; D050500:Pancreatitis, Chronic / Q000378:metabolism / Q000473:pathology*; D012313:RNA / Q000302:isolation & purification; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D012038:Regeneration; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D014162:Transfection
chemical_list: D002135:Calcium-Binding Proteins; D024042:Collagen Type I; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; C064045:delta protein; D012313:RNA; D049410:Luciferases, Renilla