title: Overexpression of interleukin-1beta in the murine pancreas results in chronic pancreatitis.
abstract: OBJECTIVE
  Chronic pancreatitis is a significant cause of morbidity and a known risk factor for pancreatic adenocarcinoma. Interleukin-1beta is a proinflammatory cytokine involved in pancreatic inflammation. We sought to determine whether targeted overexpression of interleukin-1beta in the pancreas could elicit localized inflammatory responses and chronic pancreatitis.
  
  
  METHODS
  We created a transgenic mouse model (elastase sshIL-1beta) in which the rat elastase promoter drives the expression of human interleukin-1beta. Mice were followed up for up to 2 years. Pancreata of elastase sshIL-1beta mice were analyzed for chronic pancreatitis-associated histologic and molecular changes. To study the potential effect of p53 mutation in chronic pancreatitis, elastase sshIL-1beta mice were crossed with p53(R172H) mice.
  
  
  RESULTS
  Three transgenic lines were generated, and in each line the pancreas was atrophic and occasionally showed dilation of pancreatic and biliary ducts secondary to proximal fibrotic stenosis. Pancreatic histology showed typical features of chronic pancreatitis. There was evidence for increased acinar proliferation and apoptosis, along with prominent expression of tumor necrosis factor-alpha; chemokine (C-X-C motif) ligand 1; stromal cell-derived factor 1; transforming growth factor-beta1; matrix metallopeptidase 2, 7, and 9; inhibitor of metalloproteinase 1; and cyclooxygenase 2. The severity of the lesions correlated well with the level of human interleukin-1beta expression. Older mice displayed acinar-ductal metaplasia but did not develop mouse pancreatic intraepithelial neoplasia or tumors. Elastase sshIL-1beta*p53(R172H/+) mice had increased frequency of tubular complexes, some of which were acinar-ductal metaplasia.
  
  
  CONCLUSIONS
  Overexpression of interleukin-1beta in the murine pancreas induces chronic pancreatitis. Elastase sshIL-1beta mice consistently develop severe chronic pancreatitis and constitute a promising model for studying chronic pancreatitis and its relationship with pancreatic adenocarcinoma.
authors.affiliation: Division of Digestive and Liver Diseases, Columbia University Medical Center, New York 10032, USA.
authors.forename: Frederic
authors.initials: F
authors.lastname: Marrache
authors.forename: Shui Ping
authors.initials: SP
authors.lastname: Tu
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.forename: Swaroop
authors.initials: S
authors.lastname: Pendyala
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Osterreicher
authors.forename: Shanisha
authors.initials: S
authors.lastname: Gordon
authors.forename: Vigneshwaran
authors.initials: V
authors.lastname: Ramanathan
authors.forename: Melitta
authors.initials: M
authors.lastname: Penz-Osterreicher
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Betz
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Song
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D010179:Pancreas / Q000473:pathology / Q000503:physiopathology*; D010196:Pancreatic Elastase / Q000235:genetics; D050500:Pancreatitis, Chronic / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D012720:Severity of Illness Index
chemical_list: D053583:Interleukin-1beta; D010196:Pancreatic Elastase
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