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Regulation of NK Cell Function by Human Granulocyte Arginase¹

Johanna Oberlies^*,, Carsten Watzl, Thomas Giese, Claudia Luckner^*,, Pascale Kropf, Ingrid Müller, Anthony D. Ho^* and Markus Munder^2,*,

^* Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany; Institute of Immunology, University of Heidelberg, Heidelberg, Germany; and Department of Immunology, Faculty of Medicine, Imperial College London, United Kingdom

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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Deutsche Forschungsgemeinschaft (MU1547/3-1) and in part by the Hopp-Foundation.

² Address correspondence and reprint requests to Dr. Markus Munder, Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. E-mail address: Markus_Munder{at}med.uni-heidelberg.de

³ Abbreviations used in this paper: PMN, polymorphonuclear granulocytes; Arg(–) medium, arginine-free medium; Arg(+) medium, medium containing 1mM arginine; L-NMMA, N^G-monomethyl-L-arginine; nor-NOHA, N-hydroxy-nor-L-arginine; NOS, nitric oxide synthase; PI, propidium iodide; PMN-S, PMN sonicate; PUS-SN, cell-free supernatant of human pus; TAM, tumor-associated macrophage.