Overexpression of interleukin-1beta in the murine pancreas results in chronic pancreatitis.
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.
Marrache
Frederic
F
Division of Digestive and Liver Diseases, Columbia University Medical Center, New York 10032, USA.
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
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
D053583:Interleukin-1beta; D010196:Pancreatic Elastase
Dig Dis. 2007;25(3):282-4
17827958
Cold Spring Harb Symp Quant Biol. 2005;70:65-72
16869739
Gastroenterology. 2006 Dec;131(6):1844-55
17087933
EMBO J. 1997 May 15;16(10):2621-33
9184209
Am J Physiol Gastrointest Liver Physiol. 2002 Jun;282(6):G1105-12
12016137
Am J Respir Cell Mol Biol. 2005 Apr;32(4):311-8
15668323
Am J Pathol. 2004 Apr;164(4):1481-93
15039235
JAMA. 2001 Jul 11;286(2):169-70
11448279
Cancer Cell. 2007 Mar;11(3):291-302
17349585
Dig Dis Sci. 2000 Apr;45(4):665-74
10759232
Am Rev Respir Dis. 1987 Jan;135(1):66-71
2948432
J Surg Res. 1996 Jun;63(1):231-6
8661203
Cell. 2004 Dec 17;119(6):847-60
15607980
J Natl Cancer Inst. 1997 Mar 19;89(6):442-6
9091646
Cancer Res. 2006 Jan 1;66(1):95-106
16397221
Gastroenterology. 1997 May;112(5):1656-63
9136845
Gastroenterology. 1997 May;112(5):1664-72
9136846
Am J Physiol Gastrointest Liver Physiol. 2004 Apr;286(4):G515-20
15010360
Nat Rev Cancer. 2002 Dec;2(12):897-909
12459728
Diabetes. 2001 Jul;50(7):1553-61
11423476
Cancer Cell. 2005 May;7(5):469-83
15894267
Gastroenterology. 2000 Mar;118(3):582-90
10702210
J Clin Invest. 1999 Jun;103(11):1587-95
10359568
Development. 2005 Aug;132(16):3767-76
16020518
Cancer Cell. 2007 Mar;11(3):229-43
17349581
Cancer Cell. 2005 Sep;8(3):185-95
16169464
Genes Dev. 2006 Nov 15;20(22):3147-60
17114585
J Clin Invest. 2007 Jan;117(1):50-9
17200706
Gastroenterology. 2007 Apr;132(4):1557-73
17466744
N Engl J Med. 1993 May 20;328(20):1433-7
8479461
Cell Immunol. 1996 May 1;169(2):226-37
8620550
Gut. 2002 Dec;51(6):849-52
12427788
Genes Dev. 2006 Nov 15;20(22):3130-46
17114584
Immunology. 1999 Jan;96(1):128-37
10233687
Arch Histol Cytol. 1995 Aug;58(3):365-74
8527243
J Clin Invest. 2004 May;113(10):1398-407
15146237
J Exp Med. 2003 Sep 15;198(6):877-88
12975454
Mol Cell. 2001 Jun;7(6):1153-63
11430819
Gastroenterology. 2006 Dec;131(6):1856-69
17123526