Overexpression of interleukin-1beta in the murine pancreas results in chronic pancreatitis.

BACKGROUND & AIMS 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.

[1]  G. Manes,et al.  Risk Factors of Chronic Pancreatitis , 2007, Digestive Diseases.

[2]  H. Witt,et al.  Chronic pancreatitis: challenges and advances in pathogenesis, genetics, diagnosis, and therapy. , 2007, Gastroenterology.

[3]  R. Hruban,et al.  Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. , 2007, Cancer cell.

[4]  M. Barbacid,et al.  Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. , 2007, Cancer cell.

[5]  M. Omary,et al.  The pancreatic stellate cell: a star on the rise in pancreatic diseases. , 2007, The Journal of clinical investigation.

[6]  M. Hebrok,et al.  Primary cilia deletion in pancreatic epithelial cells results in cyst formation and pancreatitis. , 2006, Gastroenterology.

[7]  Gerald C. Chu,et al.  Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. , 2006, Genes & development.

[8]  H. Moses,et al.  Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression. , 2006, Genes & development.

[9]  R. DePinho,et al.  Pten constrains centroacinar cell expansion and malignant transformation in the pancreas. , 2005, Cancer cell.

[10]  S. Leach,et al.  Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates , 2005, Development.

[11]  R. Hruban,et al.  Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. , 2005, Cancer cell.

[12]  J. Tichelaar,et al.  Interleukin-1beta causes pulmonary inflammation, emphysema, and airway remodeling in the adult murine lung. , 2005, American journal of respiratory cell and molecular biology.

[13]  T. Jacks,et al.  Mutant p53 Gain of Function in Two Mouse Models of Li-Fraumeni Syndrome , 2004, Cell.

[14]  J. Lloreta,et al.  Diabetes and exocrine pancreatic insufficiency in E2F1/E2F2 double-mutant mice. , 2004, The Journal of clinical investigation.

[15]  C. Ackerley,et al.  Characteristic multiorgan pathology of cystic fibrosis in a long-living cystic fibrosis transmembrane regulator knockout murine model. , 2004, The American journal of pathology.

[16]  E. El-Omar,et al.  Inflammation and Cancer II. Role of chronic inflammation and cytokine gene polymorphisms in the pathogenesis of gastrointestinal malignancy. , 2004, American journal of physiology. Gastrointestinal and liver physiology.

[17]  Y. Iwakura,et al.  IL-1 Plays an Important Role in Lipid Metabolism by Regulating Insulin Levels under Physiological Conditions , 2003, The Journal of experimental medicine.

[18]  P. Ruszniewski,et al.  Risk of pancreatic adenocarcinoma in chronic pancreatitis , 2002, Gut.

[19]  R. DePinho,et al.  Pancreatic cancer biology and genetics , 2002, Nature Reviews Cancer.

[20]  J. Devière,et al.  Endogenous interleukin-10 modulates fibrosis and regeneration in experimental chronic pancreatitis. , 2002, American journal of physiology. Gastrointestinal and liver physiology.

[21]  M. Lerch,et al.  Cigarette smoking as a risk factor for pancreatic cancer in patients with hereditary pancreatitis. , 2001, JAMA.

[22]  O. Madsen,et al.  Improved glucose tolerance and acinar dysmorphogenesis by targeted expression of transcription factor PDX-1 to the exocrine pancreas. , 2001, Diabetes.

[23]  D. Ron,et al.  Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. , 2001, Molecular cell.

[24]  B. Neuschwander‐Tetri,et al.  Repetitive Self-Limited Acute Pancreatitis Induces Pancreatic Fibrogenesis in the Mouse , 2000, Digestive Diseases and Sciences.

[25]  O. Moine,et al.  CD4(+ )T cells play an important role in acute experimental pancreatitis in mice. , 2000, Gastroenterology.

[26]  M. Vidal,et al.  Exocrine pancreatic disorders in transsgenic mice expressing human keratin 8. , 1999, The Journal of clinical investigation.

[27]  Björkdahl,et al.  Lymphoid hyperplasia in transgenic mice over‐expressing a secreted form of the human interleukin‐1β gene product , 1999, Immunology.

[28]  L. Wakefield,et al.  Expression of a dominant‐negative mutant TGF‐β type II receptor in transgenic mice reveals essential roles for TGF‐β in regulation of growth and differentiation in the exocrine pancreas , 1997 .

[29]  M. Löhr,et al.  Pancreatic fibrosis in experimental pancreatitis induced by dibutyltin dichloride. , 1997, Gastroenterology.

[30]  H. Friess,et al.  Cytotoxic cells are activated in cellular infiltrates of alcoholic chronic pancreatitis. , 1997, Gastroenterology.

[31]  E. Dimagno,et al.  Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. , 1997, Journal of the National Cancer Institute.

[32]  G. Carter,et al.  Transgenic animals demonstrate a role for the IL-1 receptor in regulating IL-1beta gene expression at steady-state and during the systemic stress induced by acute pancreatitis. , 1996, The Journal of surgical research.

[33]  U. Andersson,et al.  Fusion of a signal sequence to the interleukin-1 beta gene directs the protein from cytoplasmic accumulation to extracellular release. , 1996, Cellular immunology.

[34]  H. Katoh,et al.  Changes in the mouse exocrine pancreas after pancreatic duct ligation: a qualitative and quantitative histological study. , 1995, Archives of histology and cytology.

[35]  A. Andrén-sandberg,et al.  Pancreatitis and the risk of pancreatic cancer , 1993 .

[36]  D. Bar-Sagi,et al.  A mouse model of hereditary pancreatitis generated by transgenic expression of R122H trypsinogen. , 2006, Gastroenterology.

[37]  E. Furth,et al.  Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations. , 2006, Cancer research.

[38]  D. Tuveson,et al.  Ductal pancreatic cancer in humans and mice. , 2005, Cold Spring Harbor symposia on quantitative biology.

[39]  G. Hunninghake,et al.  Interleukin-1 is a chemotactic factor for human T-lymphocytes. , 1987, The American review of respiratory disease.