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Animal Model |
2-Macroglobulin- and Murinoglobulin-1- Deficient Mice
From the Experimental Genetics Group, Center for Human Genetics, Flemish Institute for Biotechnology, Leuven, Belgium
Mice deficient in either or both mouse 
2-macroglobulin (MAM) and
murinoglobulin-1 (MUG1) were generated and proved phenotypically normal
under standard conditions. Acute pancreatitis was induced with a diet
deficient in choline and methionine, supplemented with
ethionine. The mortality was less than 25% in wild-type mice,
as opposed to at least 56% in knockout mice, and was highest
(70%) in MAM-/- mice, with earliest onset at 2 days. Plasma
amylase and lipase levels were increased, but pancreatic tissue
appeared histologically variable in individual mice. The clinical
symptoms were most severe in MAM-/- mice and,
surprisingly, were not aggravated in the double knockout
mice, suggesting that the lack of proteinase inhibition
capacity was not the major problem. Therefore, we analyzed the
expression of 21 different cytokines and polypeptide factors in the
pancreas of all experimental groups of mice. Interleukin-1-receptor
antagonist mRNA was consistently induced by the diet in the pancreas of
MAM-/- mice, and transforming growth factor-ß,
tumor necrosis factor-, tumor necrosis factor-ß,
ß-lymphotoxin, and interferon-
mRNA levels were also
increased. The data demonstrate the important role of
2-macroglobulin (A2M) in acute pancreatitis as both a
proteinase inhibitor and a cytokine carrier. Mice deficient in MAM
and/or MUG thus offer new experimental models for defining in
vivo the role of the macroglobulins in pancreatitis and in
other normal and pathological processes.
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