Abstract
The mouse alpha 2-macroglobulin gene was inactivated in embryonic stem cells by homologous recombination. Liver alpha 2-macroglobulin mRNA and plasma protein was absent in homozygotes and reduced to 50% in heterozygotes. alpha 2-Macroglobulin-deficient mice were viable and produced normally sized litters with normal sex ratio over 3 generations. Characterization of adult homozygotes included diets with different fat content, treatments with endotoxin, bleomycin, carbon tetrachloride, and ethionine to test for immune system, lung, liver, and pancreas toxicity, respectively. Knock-out mice were more resistant to endotoxin but more sensitive to a choline-free diet supplemented with ethionine. Regulation of murinoglobulin mRNA expression during pregnancy was analyzed as a possible back-up mechanism for the deficiency in alpha 2-macroglobulin. In addition, expression of mRNA was studied, coding for alpha 2-macroglobulin receptor/lipoprotein receptor-related protein, low density lipoprotein receptor, and very low density lipoprotein receptor and for some common ligands, i.e. apolipoprotein E, lipoprotein lipase, and the 44-kDa heparin binding protein. Their differential regulation in the knock-out mice relative to C57B1 mice was evident and is discussed. The impressive 15-fold increase in maternal liver murinoglobulin mRNA at partum in the knock-out mice indicated increased consumption, compared to only 4-fold in normal mice. Thus, murinoglobulin appears as the major proteinase inhibitor around partum, obviously solicited to a much greater extend in alpha 2-macroglobulin-deficient mice.
Highlights
IntroductionRegulation of murinoglobulin mRNA expression during pregnancy was analyzed as a possible back-up mechanism for the deficiency in tr2-macroglobulin
Liver tr2-macroglobulin mRNA and plasma protein was absent in homozygotes and reduced to 50% in heterozygotes. tr2-Macroglobulin-deficient mice were viable and produced normally sized litters with normal sex ratio over 3 generations
Characterization of adult homozygotes included diets with different fat content, treatments with endotoxin, bleomycin, carbon tetrachloride, and ethionine to test for immune system, lung, liver, and pancreas toxicity, respectively, Knock-out mice were more resistant to endotoxin but more sensitive to a choline-free diet supplemented with ethionine
Summary
Regulation of murinoglobulin mRNA expression during pregnancy was analyzed as a possible back-up mechanism for the deficiency in tr2-macroglobulin. Expression of mRNA was studied, coding for tr2-macroglobulin receptor/lipoprotein receptor-related protein, low density lipoprotein receptor, and very low density lipoprotein receptor and for some common ligands, i.e. apolipoprotein E, lipoprotein lipase, and the 44-kDa heparin binding protein. Their differential regulation in the knockout mice relative to C57BI mice was evident and is discussed. Murinoglobulin appears as the major proteinase inhibitor around partum, obviously solicited to a much greater extend in tr2-macroglobulin-deficient mice. The interaction of A2M with a wide range of cytokines and growth factors is not understood, it might explain some of the immunochemical and growth promoting properties ascribed to A2M [6, 7]
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