Relationship of strain-dependent susceptibility to experimentally induced acute pancreatitis with regulation of Prss1 and Spink3 expression

Abstract

To analyze susceptibility to acute pancreatitis, five mouse strains including Japanese Fancy Mouse 1 (JF1), C57BL/6J, BALB/c, CBA/J, and C3H/HeJ were treated with either a cholecystokinin analog, cerulein, or a choline-deficient, ethioninesupplemented (CDE) diet. The severity of acute pancreatitis induced by cerulein was highest in C3H/HeJ and CBA/J, moderate in BALB/c, and mildest in C57BL/6J and JF1. Basal protein expression levels of the serine protease inhibitor, Kazal type 3 (Spink3) were higher in JF1 and C57BL/6J mice than those of the other three strains under normal feeding conditions. After treatment with cerulein, expression level of Spink3 increased remarkably in JF1 and mildly in C57BL/6J, BALB/c, CBA/J, and C3H/HeJ strains. Increased proteinase, serine, 1 (Prss1) protein expression accompanied by increased trypsin activity with cerulein treatment was observed in susceptible strains such as CBA/J and C3H/HeJ. Similar results were obtained with a CDE diet. In the 3 kb Spink3 promoter region, 92 or 8 nucleotide changes were found in JF1 or C3H vs C57BL/6J, respectively, whereas in the Prss1 promoter region 39 or 46 nucleotide changes were found in JF1 or C3H vs C57BL/6J, respectively. These results suggest that regulation of Prss1 and Spink3 expression is involved in the susceptibility to experimentally induced pancreatitis. The JF1 strain, which is derived from the Japanese wild mouse, will be useful to examine new mechanisms that may not be found in other laboratory mouse strains. Over 450 inbred strains of mice have been described, 1 providing a wealth of different genotypes and phenotypes for studying human diseases. Actually, the use of various breeding strategies in combination with positional cloning and positional candidate gene approach has led to the discovery of many genes that underlie human disease. 2 The Japanese wild mouse, belonging to Mus musculus molossinus, has several genetic characteristics clearly distinguishable from the European wild mouse, derived from M.m. domesticus. These subspecies were separated about one million years ago and about 1% of their genome sequences are different. [3][4][5][6][7][8] Therefore, strains MSM/Ms 9 and Japanese Fancy Mouse 1 (JF1), 10 which were established from M.m. molossinus, are powerful genetic resources to analyze disease processes.Many inbred strains have been bred for specific phenotypes. C57BL/6J mice are susceptible to high-fat diet-induced type II diabetes. 11 JF1 mice are especially sensitive to high-fat diet-induced diabetes and obesity, whereas MSM/Ms mice are resistant. 12 To date, however, there is little information about the difference in severity of pancreatitis among inbred strains of mice.Acute pancreatitis is an important disease that can be triggered by a variety of factors, including excessive alcohol consumption, 13-16 obstruction of the ampulla of Vater by gall stones, 17,18 and genetic factors. 19,20 Hereditary chronic pancreatitis is a rare form of early onset chronic pancreatitis, characterized by the onset of recurrent...

Morphine worsens the severity and prevents pancreatic regeneration in mouse models of acute pancreatitis

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SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis-Associated Cancer

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Autoactivation of Mouse Trypsinogens Is Regulated by Chymotrypsin C via Cleavage of the Autolysis Loop

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