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

ABSTRACT: 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.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.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.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.

SUBMITTER: Marrache F

PROVIDER: S-EPMC2707078 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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

Marrache Frederic F Tu Shui Ping SP Bhagat Govind G Pendyala Swaroop S Osterreicher Christoph H CH Gordon Shanisha S Ramanathan Vigneshwaran V Penz-Osterreicher Melitta M Betz Kelly S KS Song Zhigang Z Wang Timothy C TC

Gastroenterology 20080701 4

<h4>Background & aims</h4>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.<h4>Methods</h4>We created a transgenic mouse model (elastase sshIL-1beta) in which the rat elastase promoter driv ...[more]

PMID: 18789941

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Project description:BACKGROUND:Diagnosis of early chronic pancreatitis is a clinical challenge and hindered by the lack of a gold standard. Endoscopic ultrasound (EUS) and the endoscopic pancreatic function test (ePFT) are the most sensitive morphological and functional methods in this setting. EUS-elastography allows for the quantification (strain ratio) of pancreatic fibrosis, and the dynamic evaluation of the main pancreatic duct compliance provides additional information. We developed a multimodal EUS-based approach for the evaluation of the pancreas by integrating these four methods in a single procedure. OBJECTIVE:We aim to describe morphological and functional pancreatic abnormalities in patients with clinical suspicion of chronic pancreatitis and inconclusive EUS findings by using the multimodal EUS-based approach. METHODS:This was a prospective, cross-sectional, observational study of patients with clinically suspected chronic pancreatitis and indeterminate EUS criteria of the disease. EUS criteria of chronic pancreatitis, quantitative pancreatic elastography, ePFT and compliance of the main pancreatic duct were evaluated in a single procedure. RESULTS:In total, 53 patients with 3-4 EUS criteria of chronic pancreatitis were included (mean age 39.7 years, 29 male). Strain ratio was abnormally high in all patients. Peak bicarbonate concentration was decreased in 43 patients (81.1%) and the main pancreatic duct compliance was reduced in 41 patients (77.3%). Some 34 patients (64.1%) had abnormal results at EUS, elastography, ePFT and compliance of the main pancreatic duct. CONCLUSIONS:A multimodal EUS-based test for the morphological and functional evaluation of the pancreas is presented, which allows detecting mild pancreatic abnormalities in patients with suspected early chronic pancreatitis. The presence of abnormal morphological and functional evaluation of the pancreas could support the clinical suspicion of early chronic pancreatitis in the appropriate clinical setting.

Dataset Information

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

Publications

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

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