Marrache Frederic, Tu Shui Ping, Bhagat Govind, Pendyala Swaroop, Osterreicher Christoph H, Gordon Shanisha, Ramanathan Vigneshwaran, Penz-Osterreicher Melitta, Betz Kelly S, Song Zhigang, Wang Timothy C
Division of Digestive and Liver Diseases, Columbia University Medical Center, New York 10032, USA.
Gastroenterology. 2008 Oct;135(4):1277-87. doi: 10.1053/j.gastro.2008.06.078. Epub 2008 Jul 1.
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.
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.
慢性胰腺炎是发病的重要原因，也是胰腺腺癌的已知危险因素。白细胞介素-1β是一种参与胰腺炎症的促炎细胞因子。我们试图确定胰腺中白细胞介素-1β的靶向过表达是否会引发局部炎症反应和慢性胰腺炎。
我们创建了一种转基因小鼠模型（弹性蛋白酶sshIL-1β），其中大鼠弹性蛋白酶启动子驱动人白细胞介素-1β的表达。对小鼠进行长达2年的随访。分析弹性蛋白酶sshIL-1β小鼠的胰腺是否存在与慢性胰腺炎相关的组织学和分子变化。为了研究p53突变在慢性胰腺炎中的潜在作用，将弹性蛋白酶sshIL-1β小鼠与p53（R172H）小鼠杂交。
产生了三个转基因品系，每个品系的胰腺均萎缩，偶尔因近端纤维化狭窄继发胰腺和胆管扩张。胰腺组织学表现为慢性胰腺炎的典型特征。有证据表明腺泡细胞增殖和凋亡增加，同时肿瘤坏死因子-α、趋化因子（C-X-C基序）配体1、基质细胞衍生因子1、转化生长因子-β1、基质金属蛋白酶2、7和9、金属蛋白酶抑制剂1以及环氧化酶2的表达显著。病变的严重程度与人类白细胞介素-1β的表达水平密切相关。老年小鼠出现腺泡-导管化生，但未发生小鼠胰腺上皮内瘤变或肿瘤。弹性蛋白酶sshIL-1β*p53（R172H/+）小鼠的管状复合体频率增加，其中一些是腺泡-导管化生。
小鼠胰腺中白细胞介素-1β的过表达可诱导慢性胰腺炎。弹性蛋白酶sshIL-1β小鼠持续发生严重的慢性胰腺炎，是研究慢性胰腺炎及其与胰腺腺癌关系的有前景的模型。
