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

Abstract

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.

• Authors: Frederic Marrache, Shui Ping Tu, Govind Bhagat, Swaroop Pendyala, Christoph H Osterreicher, Shanisha Gordon, Vigneshwaran Ramanathan, Melitta Penz-Osterreicher, Kelly S Betz, Zhigang Song, Timothy C Wang
• Journal: Gastroenterology (Gastroenterology) Vol. 135 Issue 4 Pg. 1277-87 (Oct 2008) ISSN: 1528-0012 [Electronic] United States
• PMID: 18789941 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-1beta
• Pancreatic Elastase

Topics

• Animals
• Disease Models, Animal
• Female
• Fibrosis
• Gene Expression (physiology)
• Humans
• Interleukin-1beta (genetics)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred CBA
• Mice, Transgenic
• Pancreas (pathology, physiopathology)
• Pancreatic Elastase (genetics)
• Pancreatitis, Chronic (genetics, pathology, physiopathology)
• Phenotype
• Promoter Regions, Genetic (genetics)
• Rats
• Severity of Illness Index