Arginase is a metabolic enzyme present in two isoforms that hydrolyse L-arginine to urea and ornithine. In humans, arginase isoform 1 is also expressed in cells of the myeloid lineage. Arginase activity promotes tumor growth and inhibits T lymphocyte activation. However the two arginase transgenic mouse lines produced so far failed to show such effects. We have generated, in two different genetic backgrounds, transgenic mice constitutively expressing arginase 1 under the control of the CD68 promoter in macrophages and monocytes. Both heterozygous and homozygous transgenic mice showed a relevant increase in mortality at early age, compared to wild type siblings (67/267 and 48/181 vs 8/149 respectively, both P<0.005). This increase was due to high incidence of hematologic malignancies, in particular myeloid leukaemia, myeloid dysplasia, lymphomas, and disseminated intravascular coagulation, diseases that were absent in wild-type mice. Atrophy of lymphoid organs due to reduction in T-cell compartment was also detected. Our results indicate that arginase activity may participate in the pathogenesis of lympho and myeloproliferative disorders, suggest the involvement of alterations of L-arginine metabolism in the onset of disseminated intravascular coagulation, and confirm a role for the enzyme in regulating T cell homeostasis.

Transgenic mice overexpressing Arginase1 in monocytic cell lineage are affected by lymphomyeloproliferative disorders and disseminated intravascular coagulation

Bronte, Vincenzo;
2015-01-01

Abstract

Arginase is a metabolic enzyme present in two isoforms that hydrolyse L-arginine to urea and ornithine. In humans, arginase isoform 1 is also expressed in cells of the myeloid lineage. Arginase activity promotes tumor growth and inhibits T lymphocyte activation. However the two arginase transgenic mouse lines produced so far failed to show such effects. We have generated, in two different genetic backgrounds, transgenic mice constitutively expressing arginase 1 under the control of the CD68 promoter in macrophages and monocytes. Both heterozygous and homozygous transgenic mice showed a relevant increase in mortality at early age, compared to wild type siblings (67/267 and 48/181 vs 8/149 respectively, both P<0.005). This increase was due to high incidence of hematologic malignancies, in particular myeloid leukaemia, myeloid dysplasia, lymphomas, and disseminated intravascular coagulation, diseases that were absent in wild-type mice. Atrophy of lymphoid organs due to reduction in T-cell compartment was also detected. Our results indicate that arginase activity may participate in the pathogenesis of lympho and myeloproliferative disorders, suggest the involvement of alterations of L-arginine metabolism in the onset of disseminated intravascular coagulation, and confirm a role for the enzyme in regulating T cell homeostasis.
Arginase , lymphomyeloproliferative disorders, T cell
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/926979
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