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1.
J Immunol ; 182(9): 5259-67, 2009 May 01.
Article in English | MEDLINE | ID: mdl-19380772

ABSTRACT

The arginine-hydrolyzing enzyme arginase is constitutively expressed by human polymorphonuclear granulocytes (PMN). Upon PMN cell death arginase is liberated and depletes arginine in the microenvironment. This amino acid depletion suppresses T cell proliferation and cytokine secretion and emerges as a key mechanism of immunosuppression during chronic inflammation and tumor growth. Here we show that PMN arginase also severely impairs key functions of primary human NK cells as well as IL-2-activated NK cells. In the absence of arginine, NK cell proliferation and IL-12/IL-18-induced secretion of IFN-gamma are severely diminished. In contrast, NK cell viability, granule exocytosis, and cytotoxicity are independent of extracellular arginine. The mechanism of NK cell suppression by arginine depletion is posttranscriptional since mRNA transcript frequency is unaffected upon NK cell activation in the absence of arginine. Finally, we demonstrate that human purulent exudate ex vivo inhibits NK cell functions exclusively due to liberated arginase. Arginase inhibitors are therefore promising pharmacological agents to treat unwanted suppression of the innate (NK cell) as well as the adaptive (T cell) immune system.


Subject(s)
Arginase/physiology , Cytotoxicity, Immunologic/immunology , Immunosuppression Therapy , Killer Cells, Natural/enzymology , Killer Cells, Natural/immunology , Lymphocyte Activation/immunology , Neutrophils/enzymology , Neutrophils/immunology , Arginine/deficiency , Arginine/physiology , Cell Proliferation , Cell Survival/immunology , Cells, Cultured , Exocytosis/immunology , Growth Inhibitors/physiology , Humans , K562 Cells , Killer Cells, Natural/cytology , Killer Cells, Natural/metabolism , Neutrophils/metabolism
2.
Blood ; 108(5): 1627-34, 2006 Sep 01.
Article in English | MEDLINE | ID: mdl-16709924

ABSTRACT

Chronic inflammation is accompanied by impaired T-cell immunity. In the mouse, myeloid cell-associated arginase accounts for the suppression of immune reactivity in various models of tumor growth and chronic infections. Here we show that arginase I is liberated from human granulocytes, and very high activities accumulate extracellularly during purulent inflammatory reactions. Human granulocyte arginase induces a profound suppression of T-cell proliferation and cytokine synthesis. This T-cell phenotype is due to arginase-mediated depletion of arginine in the T-cell environment, which leads to CD3zeta chain down-regulation but does not alter T-cell viability. Our study therefore demonstrates that human granulocytes possess a previously unanticipated immunosuppressive effector function. Human granulocyte arginase is a promising pharmacologic target to reverse unwanted immunosuppression.


Subject(s)
Arginase/pharmacology , Granulocytes/enzymology , Lymphocyte Activation/immunology , T-Lymphocytes/immunology , Arginase/genetics , Arginine/metabolism , Humans , Immunosuppression Therapy/methods , Lymphocyte Activation/drug effects , Neutrophils/enzymology , Neutrophils/immunology , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocytes/drug effects
3.
Blood ; 105(6): 2549-56, 2005 Mar 15.
Article in English | MEDLINE | ID: mdl-15546957

ABSTRACT

The balance of arginine metabolism via nitric oxide synthase (NOS) or arginase is an important determinant of the inflammatory response of murine macrophages and dendritic cells. Here we analyzed the expression of the isoform arginase I in human myeloid cells. Using healthy donors and patients with arginase I deficiency, we found that in human leukocytes arginase I is constitutively expressed only in granulocytes and is not modulated by a variety of proinflammatory and anti-inflammatory stimuli in vitro. We demonstrate that arginase I is localized in azurophil granules of neutrophils and constitutes a novel antimicrobial effector pathway, likely through arginine depletion in the phagolysosome. Our findings demonstrate important differences between murine and human leukocytes with respect to regulation and function of arginine metabolism via arginase.


Subject(s)
Antifungal Agents/metabolism , Arginase/metabolism , Gene Expression Regulation, Enzymologic/physiology , Neutrophils/enzymology , Nitric Oxide Synthase/metabolism , Secretory Vesicles/enzymology , Animals , Arginine , Humans , Hyperargininemia , Isoenzymes/metabolism , Macrophages/enzymology , Macrophages/ultrastructure , Mice , Microscopy, Electron, Transmission , Neutrophils/ultrastructure , Nitric Oxide Synthase/deficiency , Phagosomes/enzymology , Phagosomes/ultrastructure , Secretory Vesicles/ultrastructure , Species Specificity
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