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alpha2-macroglobulin- and murinoglobulin-1- deficient mice. A mouse model for acute pancreatitis
L Umans1, L Serneels, L Overbergh
1Experimental Genetics Group, Center for Human Genetics, Flemish Institute for Biotechnology, Leuven, Belgium.
Abstract:
Mice deficient in either or both mouse alpha2-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-beta, tumor necrosis factor-alpha, tumor necrosis factor-beta, beta-lymphotoxin, and interferon-gamma mRNA levels were also increased. The data demonstrate the important role of alpha2-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.
Insights
Mice lacking alpha2-macroglobulin (A2M) showed increased mortality and severity in acute pancreatitis. This suggests A2M plays a crucial role in managing this condition.
Area of Science:
- Biochemistry
- Immunology
- Gastroenterology
Background:
- Alpha2-macroglobulin (A2M) is a key proteinase inhibitor.
- The role of A2M and murinoglobulin-1 (MUG1) in acute pancreatitis is not fully understood.
- Mouse models deficient in these macroglobulins can provide insights into pancreatitis pathogenesis.
Purpose of the Study:
- To investigate the role of mouse alpha2-macroglobulin (MAM) and murinoglobulin-1 (MUG1) in acute pancreatitis.
- To establish and characterize knockout mouse models for studying pancreatitis.
- To elucidate the mechanisms by which MAM influences pancreatitis severity.
Main Methods:
- Generated knockout mice deficient in MAM and/or MUG1.
- Induced acute pancreatitis using a choline-methionine-deficient diet supplemented with ethionine.
- Assessed mortality, clinical symptoms, plasma enzyme levels, and pancreatic histology.
- Analyzed the expression of cytokines and polypeptide factors in pancreatic tissue.
Main Results:
- Mice deficient in MAM and/or MUG1 exhibited significantly higher mortality rates compared to wild-type mice.
- MAM-/- mice showed the highest mortality and earliest onset of pancreatitis.
- Cytokine mRNA levels, including IL-1RA, TGF-β, TNF-α, and IFN-γ, were elevated in the pancreas of MAM-/- mice.
- Surprisingly, double knockout mice did not show exacerbated symptoms, suggesting proteinase inhibition capacity wasn't the sole factor.
Conclusions:
- Alpha2-macroglobulin (A2M) plays a critical role in acute pancreatitis, acting as both a proteinase inhibitor and a cytokine carrier.
- Mice deficient in MAM and/or MUG1 serve as valuable experimental models for in vivo studies of pancreatitis.
- Further research using these models can define the in vivo functions of macroglobulins in pancreatitis and other biological processes.